The present invention provides non-steroidal compounds which are selective modulators (i.e., agonists and antagonists) of a steroid receptor, specifically, the glucocorticoid receptor. The present invention also provides pharmaceutical compositions containing these compounds and methods for using these compounds to treat animals requiring glucocorticoid receptor agonist and/or antagonist therapy. Glucocorticoid receptor modulators are useful to treat diseases, such as obesity, diabetes, inflammation and others as described below. The present invention also provides intermediates and processes for preparing these compounds.
Nuclear receptors are classically defined as a family of ligand dependent transcription factors, that are activated in response to ligand binding (R. M. Evans, 240 Science, 889 (1988)). Members of this family include the following receptors: glucocorticoid, mineralocorticoid, androgen, progesterone and estrogen. Naturally occurring ligands to these receptors are low molecular weight molecules that play an important role in health and in many diseases. Excesses or deficiencies of these ligands can have profound physiological consequences. As an example, glucocorticoid excess results in Cushing""s Syndrome, while glucocorticoid insufficiency results in Addison""s Disease.
The glucocorticoid receptor (GR) is present in glucocorticoid responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it specifically interacts with DNA and/or protein(s) and regulates transcription in a glucocorticoid responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFxcexa-B. Such interactions result in inhibition of API- and NFxcexa-B-mediated transcription and are believed to be responsible for some of the anti-inflammatory activity of endogenously administered glucocorticoids. In addition, glucocorticoids may also exert physiologic effects independent of nuclear transcription. Biologically relevant glucocorticoid receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid receptor agonists exist including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and eliciting GR mediated events, including transcription. RU486 is an example of a non-selective glucocorticoid receptor antagonist.
U.S. Pat. No. 3,683,091 discloses phenanthrene compounds, specifically certain di-7-hydroxy or methyl-2,3,4,4a,9,10-hexahydrophenanthren-2-one and 4a-alkyl derivatives, hydrogenated derivatives, functional derivatives and optically active isomers thereof useful as specific anti-acne agents.
Japanese Patent Application, Publication No. 45014056, published May 20, 1970, discloses the manufacture of 1,2,3,4,9,10,11xcex1, 12-octahydro-7-methoxy-12xcex2-butylphenanthren-2xcex2-ol and certain of its derivatives useful as antiandrogenic and antianabolic drugs.
Japanese Patent Application, Publication No. 6-263688, published Sep. 20, 1994, discloses certain phenanthrene derivatives which are interleukin-1 (IL-1) inhibitors. It also discloses their preparation and certain intermediates thereto. International Patent Application Publication No. WO 95/10266, published Apr. 20, 1995, discloses the preparation and formulation of certain phenanthrene derivatives as nitrogen monoxide synthesis inhibitors.
Japanese Patent Application, Publication No. 45-36500, published Nov. 20, 1970, discloses a method of making certain optically active phenanthrene derivatives which are useful as antiandrogenic agents.
European Patent Application, Publication No. 0 188 396, published Jul. 23, 1986, discloses certain substituted steroid compounds, certain processes and intermediates for preparing them, their use and pharmaceutical compositions containing them. These compounds are disclosed to possess antiglucocorticoid activity, and some of them have glucocorticoid activity.
C. F. Bigge et al., J. Med. Chem. 1993, 36, 1977-1995, discloses the synthesis and pharmacolgical evaluation of a series of octahydrophenanthrenamines and certain of their heterocyclic analogues as potential noncompetitive antagonists of the N-methyl-D-aspartate receptor complex.
P. R. Kanjilal et al., J. Org. Chem. 1985, 50, 857-863, discloses synthetic studies toward the preparation of certain complex diterpenoids.
G. Sinha et al., J. Chem. Soc., Perkin Trans. I (1983), (10), 2519-2528, discloses the synthesis of the isomeric bridged diketones cis-3,4,4a,9,10,10a-hexahydro-1,4a-ethanophenanthren-2(1H),12-dione and trans-3,4,4a,9,10,10a-hexahydro-3,4a-ethanophenanthren-2(1H),1,2-dione by highly regioselective intramolecular aldol condensations through the stereochemically defined cis- and trans-2,2-ethylenedioxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-4a-ylacetaldehydes.
U. R. Ghatak, M. Sarkar and S. K. Patra, Tetrahedron Letters No. 32, pp. 2929-2931, 1978, discloses a simple stereospecific route to certain polycyclic bridged-ring intermediates useful in preparing some complex diterpenoids.
P. N. Chakrabortty et al., Indian J. Chem. (1974), 12(9), 948-55, discloses the synthesis of 1xcex1-methyl-1xcex2,4axcex2-dicarboxy-1,2,3,4,4a,9,10,10axcex2-octahydro-phenanthrene, an intermediate in the synthesis of certain diterpenoids and diterpene alkaloids, and of 1xcex2,4axcex2-dicarboxy-1,2,3,4,4a,9,10,10axcex2-octahydrophenanthrene.
E. Fujita et al., J. Chem. Soc., Perkin Trans. I (1974), (1), 165-77, discloses the preparation of enmein from 5-methoxy-2-tetralone via ent-3-xcex2,2-epoxy-3-methoxy-17-norkaurane-6xcex1,16xcex1-diol.
H. Sdassi et al., Synthetic Communications, 25(17), 2569-2573 (1995) discloses the enantioselective synthesis of (R)-(+)-4a-cyanomethyl-6-methoxy-3,4,9,10-tetrahydrophenanthren-2-one, which is a key intermediate in morphinan synthesis.
T. Ibuka et al., Yakugaku Zasshi (1967), 87(8), 1014-17, discloses certain alkaloids of menispermaceous plants.
Japanese Patent 09052899, dated Feb. 25, 1997, discloses certain diterpene or triterpene derivatives which are leukotriene antagonists obtained by extraction from Tripterygium wilfordii for therapeutic use.
U.S. Pat. No. 5,696,127 discloses certain nonsteroidal compounds, such as 5H-chromeno[3,4-f]quinolines, which are selective modulators of steroid receptors.
U.S. Pat. No. 5,767,113 discloses certain synthetic steroid compounds useful for concurrently activating glucocorticoid-induced response and reducing multidrug resistance.
Published European Patent Application 0 683 172, published Nov. 11, 1995, discloses certain 11,21-bisphenyl-19-norpregnane derivatives having anti-glucocorticoid activity and which can be used to treat or prevent glucocorticoid dependent diseases.
D. Bonnet-Delpon et al., Tetrahedron (1996), 52(1), 59-70, discloses certain CF3-substituted alkenes as good partners in Diels-Alder reactions with Danishefsky""s diene and in 1,3-dipolar cycloadditions with certain nitrones and non-stabilized azomethine ylides.
International Patent Application Publication No. WO 98/26783, published Jun. 25, 1998, discloses the use of certain steroid compounds with anti-glucocorticoid activity, with the exception of mifepristone, for preparing medicaments for the prevention or treatment of psychoses or addictive behavior.
International Patent Application Publication No. WO 98/27986, published Jul. 2, 1998, discloses methods for treating non-insulin dependent Diabetes Mellitus (NIDDM), or Type II Diabetes, by administering a combination of treatment agents exhibiting glucocorticoid receptor type I agonist activity and glucocorticoid receptor type II antagonist activity. Treatment agents such as certain steroid compounds having both glucocorticoid receptor type I agonist activity and glucocorticoid receptor type II antagonist activity are also disclosed.
International Patent Application Publication No. WO 98/31702, published Jul. 23, 1998, discloses certain 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene derivatives useful in the treatment or prophylaxis of glucocorticoid dependent diseases or symptoms.
Published European Patent Application 0 903 146, published Mar. 24, 1999, discloses that the steroid 21-hydroxy-6,19-oxidoprogesterone (21OH-6OP) has been found to be a selective antiglucocorticoid and is used for the treatment of diseases associated with an excess of glucocorticoids in the body, such as the Cushing""s syndrome or depression.
All of the above cited patents and published patent applications are hereby incorporated by reference herein in their entirety.
J. A. Findlay et al, Tetrahedron Letters No. 19, pp. 869-872, 1962, discloses certain intermediates in the synthesis of diterpene alkaloids.
Although there are glucocorticoid receptor therapies in the art, there is a continuing need for and a continuing search in this field of art for selective glucocorticoid receptor therapies. Thus, the identification of non-steroidal compounds which have specificity for one or more steroid receptors, but which have reduced or no cross-reactivity for other steroid or intracellular receptors, is of significant value in this field.
The present invention particularly provides: compounds of formula I 
isomers thereof, prodrugs of said compounds and isomers, and pharmaceutically acceptable salts of said compounds, isomers and prodrugs;
wherein m is 1 or 2;
xe2x80x94 represents an optional bond;
A is selected from the group consisting of 
G, H and I together with 2 carbon atoms from the A-ring or 2 carbon atoms from the B-ring form a 5-membered heterocyclic ring comprising one or more N, O or S atoms; provided that there is at most one of O and S per ring; J, K, L and M together with 2 carbon atoms from the B-ring forms a 6-membered heterocyclic ring comprising 1 or more N atoms;
X is a) absent, b) xe2x80x94CH2xe2x80x94, c) xe2x80x94CH(OH)xe2x80x94or d) xe2x80x94C(O)xe2x80x94;
R1 is a) xe2x80x94H, b) xe2x80x94Zxe2x80x94CF3, c) xe2x80x94(C1-C6)alkyl, d) xe2x80x94(C2-C6)alkenyl, e) xe2x80x94(C2-C6)alkynyl, f) xe2x80x94CHO, g) xe2x80x94CHxe2x95x90Nxe2x80x94OR12, h) xe2x80x94Zxe2x80x94C(O)OR12, i) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, j) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-het, k) xe2x80x94Zxe2x80x94NR12R13, l) xe2x80x94Zxe2x80x94NR12het, m) xe2x80x94Z-het, n) xe2x80x94Zxe2x80x94O-het, o) xe2x80x94Z-arylxe2x80x2, p) xe2x80x94Zxe2x80x94O-arylxe2x80x2, q) xe2x80x94CHOH-arylxe2x80x2 or r) xe2x80x94C(O)-arylxe2x80x2; wherein arylxe2x80x2 in substituents o) to r) is substituted independently with 0, 1 or 2 of the following: xe2x80x94Zxe2x80x94OH, xe2x80x94Zxe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12-het, xe2x80x94C(O)NR12R13, xe2x80x94C(O)O(C1-C6)alkyl, xe2x80x94C(O)OH, xe2x80x94C(O)xe2x80x94het, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C1-C6)alkyl, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C2-C6)alkenyl, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C2-C6)alkynyl, xe2x80x94NR12xe2x80x94C(O)xe2x80x94Z-het, xe2x80x94CN, xe2x80x94Z-het, xe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, xe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)O(C1-C6)alkyl, xe2x80x94NR12xe2x80x94Zxe2x80x94C(O)O(C1-C6)alkyl, xe2x80x94N(Zxe2x80x94C(O)O(C1-C6)alkyl)2, xe2x80x94NR12xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12xe2x80x94SO2xe2x80x94R13, xe2x80x94NR12xe2x80x94SO2-het, xe2x80x94C(O)H, xe2x80x94Zxe2x80x94NR12xe2x80x94Zxe2x80x94O(C1-C6)alkyl, xe2x80x94Zxe2x80x94NR12xe2x80x94Zxe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12xe2x80x94(C3-C6)cycloalkyl, xe2x80x94Zxe2x80x94N(Zxe2x80x94O(C1-C6)alkyl)2, xe2x80x94SO2R12, xe2x80x94SOR12, xe2x80x94SR12, xe2x80x94SO2NR12R13, xe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C4)alkyl, xe2x80x94Oxe2x80x94SO2xe2x80x94(C1-C4)alkyl, -halo or xe2x80x94CF3;
Z for each occurrence is independently a) xe2x80x94(C0-C6)alkyl, b) xe2x80x94(C2-C6)alkenyl or c) xe2x80x94(C2-C6)alkynyl;
R2 is a) xe2x80x94H, b) xe2x80x94halo, c) xe2x80x94OH, d) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 xe2x80x94OH, e) xe2x80x94NR12R13, f) xe2x80x94Zxe2x80x94C(O)O(C1-C6)alkyl, g) xe2x80x94Zxe2x80x94C(O)NR12R13, h) xe2x80x94Oxe2x80x94(C1-C6)alkyl, i) xe2x80x94Zxe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, j) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, k) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94O(C1-C6)alkyl, I) xe2x80x94Oxe2x80x94(C2-C6)alkenyl, m) xe2x80x94Oxe2x80x94(C2-C6)alkynyl, n) xe2x80x94Oxe2x80x94Z-het, o) xe2x80x94COOH, p) xe2x80x94C(OH)R12R13 or q) xe2x80x94Zxe2x80x94CN;
R3 is a) xe2x80x94H, b) xe2x80x94(C1-C10)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom is substituted with 0, 1 or 2 Ry c) xe2x80x94(C2-C10)alkenyl substituted with 0, 1 or 2 Ry, d) xe2x80x94(C2-C10)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0, 1 or 2 Ry, e) xe2x80x94CHxe2x95x90Cxe2x95x90CH2, f) xe2x80x94CN, g) xe2x80x94(C3-C6)cycloalkyl, h) xe2x80x94Z-aryl, i) xe2x80x94Z-het, j) xe2x80x94C(O)O(C1-C6)alkyl, k) xe2x80x94O(C1-C6)alkyl, l) xe2x80x94Zxe2x80x94Sxe2x80x94R12, m) xe2x80x94Zxe2x80x94S(O)xe2x80x94R12, n) xe2x80x94Zxe2x80x94S(O)2xe2x80x94R12, o) xe2x80x94CF3, p) xe2x80x94NR12Oxe2x80x94(C1-C6)alkyl or q) xe2x80x94CH2ORy.
provided that one of R2 and R3 is absent when there is a double bond between CR2R3 (the 7 position) and the F moiety (the 8 position) of the C-ring;
Ry for each occurrence is independently a) xe2x80x94OH, b) -halo, c) xe2x80x94Zxe2x80x94CF3, d) xe2x80x94Zxe2x80x94CF(C1-C3 alkyl)2, e) xe2x80x94CN, f) xe2x80x94NR12R13, g) xe2x80x94(C3-C6)cycloalkyl, h) xe2x80x94(C3-C6)cycloalkenyl, i) xe2x80x94(C0-C3)alkyl-aryl, j) -het or k) xe2x80x94N3;
or R2 and R3 are taken together to form a) xe2x95x90CHR11, b) xe2x95x90NOR11, c) xe2x95x90O, d) xe2x95x90Nxe2x80x94NR12, e) xe2x95x90Nxe2x80x94NR12xe2x80x94C(O)xe2x80x94R12, f) oxiranyl or g) 1,3-dioxolan-4-yl;
R4 and R5 for each occurrence are independently a) xe2x80x94H, b) xe2x80x94CN, c) xe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, d) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo, f) xe2x80x94Oxe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, g) xe2x80x94Oxe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, h) xe2x80x94Oxe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo, i) halo, j) xe2x80x94OH, k) (C3-C6)cycloalkyl or 1) (C3-C6)cycloalkenyl;
or R4 and R5 are taken together to form xe2x95x90O;
R6 is a) xe2x80x94H, b) xe2x80x94CN, c) xe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, d) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo or f) xe2x80x94OH;
R7 and R16 for each occurrence are independently a) xe2x80x94H, b) -halo, c) xe2x80x94CN, d) xe2x80x94(C1-C6)alkyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo or f) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo; provided that R7 is other than xe2x80x94CN or -halo when D is NR7;
or R7 and R16 are taken together to form xe2x95x90O;
R8, R9, R14 and R15 for each occurrence are independently a) xe2x80x94H, b) -halo, c) (C1-C6)alkyl substituted with 0 to 3 halo, d) xe2x80x94(C2-C6)alkenyl substituted with 0 to 3 halo, e) xe2x80x94(C2-C6)alkynyl substituted with 0 to 3 halo, f) xe2x80x94CN, g) xe2x80x94(C3-C6)cycloalkyl, h) xe2x80x94(C3-C6)cycloalkenyl, i) xe2x80x94OH, j) xe2x80x94Oxe2x80x94(C1-C6)alkyl, k) xe2x80x94Oxe2x80x94(C1-C6)alkenyl, l) xe2x80x94Oxe2x80x94(C1-C6)alkynyl, m) xe2x80x94NR12R13, n) xe2x80x94C(O)OR12 or o) xe2x80x94C(O)NR12R13;
or R8 and R9 are taken together on the C-ring to form xe2x95x90O; provided that when m is 2, only one set of R8 and R9 are taken together to form xe2x95x90O;
or R14 and R15 are taken together to form xe2x95x90O; provided that when R14 and R15 are taken together to form xe2x95x90O, D is other than CR7 and E is other than C;
R10 is a) xe2x80x94(C1-C10)alkyl substituted with 0 to 3 substituents independently selected from -halo, xe2x80x94OH and xe2x80x94N3, b) xe2x80x94(C2-C10)alkenyl substituted with 0 to 3 substituents independently selected from -halo, xe2x80x94OH and xe2x80x94N3, c) xe2x80x94C2-C10)alkynyl substituted with 0 to 3 substituents independently selected from -halo, xe2x80x94OH and xe2x80x94N3, d) -halo, e) xe2x80x94Zxe2x80x94CN, f) xe2x80x94OH, g) xe2x80x94Z-het, h) xe2x80x94Zxe2x80x94NR12R13, i) xe2x80x94Zxe2x80x94C(O)-het, j) xe2x80x94Zxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, k) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, l) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94CN, m) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-het, n) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-aryl, o) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94NR12R13, p) xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94O(C1-C6)alkyl, q) xe2x80x94(C0-C6)alkyl-C(O)OH, r) xe2x80x94Zxe2x80x94C(O)O(C1-C6)alkyl, s) xe2x80x94Zxe2x80x94Oxe2x80x94(C0-C6)alkyl-het, t) xe2x80x94Zxe2x80x94Oxe2x80x94(C0-C6)alkyl-aryl, u) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C6)alkyl substituted with 0 to 2 Rx, v) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C6)alkyl-CH(O), w) xe2x80x94Zxe2x80x94Oxe2x80x94(C1-C6)alkyl-NR12-het, x) xe2x80x94Zxe2x80x94Oxe2x80x94Z-het-Z-het, y) xe2x80x94Zxe2x80x94Oxe2x80x94Z-het-Zxe2x80x94NR12R13, z) xe2x80x94Zxe2x80x94Oxe2x80x94Z-het-C(O)-het, a1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)-het, b1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)-het-het, c1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, d1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(S)xe2x80x94NR12R13, e1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, f1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, g1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94O(C1-C6)alkyl, h1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94OH, i1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94O(C1-C6)alkyl, j1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94OH, k1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Zxe2x80x94NR12R13, l1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94Z-het, m1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12xe2x80x94SO2xe2x80x94(C1-C6)alkyl, n1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(xe2x95x90NR12)(NR12R13), o1) xe2x80x94Zxe2x80x94Oxe2x80x94Zxe2x80x94C(xe2x95x90NOR12)(NR12R13), p1) xe2x80x94Zxe2x80x94NR12xe2x80x94C(O)xe2x80x94Oxe2x80x94Zxe2x80x94NR12R13, q1) xe2x80x94Zxe2x80x94Sxe2x80x94C(O)xe2x80x94NR12R13, r1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2xe2x80x94(C1-C6)alkyl, s1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2-aryl, t1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2xe2x80x94NR12R13, u1) xe2x80x94Zxe2x80x94Oxe2x80x94SO2xe2x80x94CF3, v1) xe2x80x94Zxe2x80x94NR12C(O)OR13 or w1) xe2x80x94Zxe2x80x94NR12C(O)R13;
or R9 and R10 are taken together on the moiety of formula A-5 to form a)xe2x95x90O or b)xe2x95x90NOR12;
R11 is a) xe2x80x94H, b) xe2x80x94(C1-C5)alkyl, c) xe2x80x94(C3-C6)cycloalkyl or d) xe2x80x94(C0-C3)alkyl-aryl;
R12 and R13 for each occurrence are each independently a) xe2x80x94H, b) xe2x80x94C1-C6)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom is substituted with 0 to 6 halo, c) xe2x80x94C2-C6)alkenyl substituted with 0 to 6 halo, or d) xe2x80x94C1-C6)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0 to 6 halo;
or R12 and R13 are taken together with N to form het;
or R6 and R14 or R15 are taken together to form 1,3-dioxolanyl;
aryl is a) phenyl substituted with 0 to 3 Rx, b) naphthyl substituted with 0 to 3 Rx or c) biphenyl substituted with 0 to 3 Rx;
het is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and the nitrogen may be in the oxidized state giving the N-oxide form; and substituted with 0 to 3 Rx;
Rx for each occurrence is independently a) -halo, b) xe2x80x94OH, c) xe2x80x94(C1-C6)alkyl, d) xe2x80x94C2-C6)alkenyl, e) xe2x80x94C2-C6)alkynyl, f) xe2x80x94O(C1-C6)alkyl, g) xe2x80x94O(C2-C6)alkenyl, h) xe2x80x94O(C2-C6)alkynyl, i) xe2x80x94(C0-C6)alkyl-NR12R13, j) xe2x80x94C(O)xe2x80x94NR12R13, k) xe2x80x94Zxe2x80x94SO2R12, l)xe2x80x94Zxe2x80x94SOR12, m) xe2x80x94Zxe2x80x94SR12, n) xe2x80x94NR12xe2x80x94SO2R13, o) xe2x80x94NR12xe2x80x94C(O)xe2x80x94R13, p) xe2x80x94NR12xe2x80x94OR13, q) xe2x80x94SO2xe2x80x94NR12R13, r) xe2x80x94CN, s) xe2x80x94CF3, t) xe2x80x94C(O)(C1-C6)alkyl, u) xe2x95x90O, v) xe2x80x94Zxe2x80x94SO2-phenyl or w) xe2x80x94Zxe2x80x94SO2-hetxe2x80x2;
arylxe2x80x2 is phenyl, naphthyl or biphenyl;
hetxe2x80x2 is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle;
provided that:
1) Xxe2x80x94R1 is other than hydrogen or methyl;
2) when R9 and R10 are substituents on the A-ring, they are other than mono- or di-methoxy;
3) when R2 and R3 are taken together to form xe2x95x90CHR11 or xe2x95x90O wherein R11 is xe2x80x94O(C1-C6)alkyl, then xe2x80x94Xxe2x80x94R1 is other than (C1-C4)alkyl;
4) when R2 and R3 are taken together to form xe2x95x90O and R9 is hydrogen on the A-ring; or when R2 is hydroxy, R3 is hydrogen and R9 is hydrogen on the A-ring, then R10 is other than xe2x80x94Oxe2x80x94(C1-C6)alkyl or xe2x80x94Oxe2x80x94CH2-phenyl at the 2-position of the A-ring;
5) when Xxe2x80x94R, is (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl, R9 and R10 are other than mono-hydroxy or xe2x95x90O, including the diol form thereof, when taken together; and
6) when X is absent, R1 is other than a moiety containing a heteroatom selected from N, O or S directly attached to the juncture of the B-ring and the C-ring.
More particularly, the present invention provides: compounds of formula I, isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs;
wherein the A-ring is selected from the group consisting of: 
D is CR7, CR7R16 or O;
E is C, CR6 or N;
F is CR4, CR4R5 or O; and
X is xe2x80x94CH2xe2x80x94.
More particularly, the present invention provides: compounds of formula I, isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein D is CH2; E is CH; F is CH2; R8 is xe2x80x94H; R9 is xe2x80x94H on the C-ring; m is 2; R14 is xe2x80x94H; R15 is xe2x80x94H; and the A-ring is the moiety of formula A-1a.
More particularly, the present invention provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R2 is a) xe2x80x94OH or b) xe2x80x94Oxe2x80x94CH2-het;
R3 is a) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 of the following: xe2x80x94CF3, xe2x80x94CN, xe2x80x94(C3-C6)cycloalkyl, -phenyl or xe2x80x94N3, b) xe2x80x94Cxe2x95x90Cxe2x80x94 substituted with 1 of the following: xe2x80x94(C1-C5)alkyl, xe2x80x94Cl, xe2x80x94CF3, xe2x80x94(C3-C6)cycloalkyl, -phenyl or -benzyl; c) xe2x80x94CH2OH, d) xe2x80x94CH2O(C1-C5)alkyl wherein 1 carbon atom may optionally be replaced with 1 oxygen atom, e) xe2x80x94CH2O(C2-C5)alkenyl, f) xe2x80x94CH2O(C2-C5)alkynyl wherein 1 carbon atom may optionally be replaced with 1 oxygen atom, g) xe2x80x94CH2ORy, h) xe2x80x94CN or i) xe2x80x94CF3;
Ry is a) xe2x80x94(C1-C3)alkyl xe2x80x94CF3, b) xe2x80x94(C3-C6)cycloalkyl, c) -phenyl or d) -benzyl;
or R2 and R3 are taken together to form a) -1,3-dioxolan-4-yl or b) xe2x95x90NOR11;
R11 is a) xe2x80x94H, b) xe2x80x94(C1-C5)alkyl, c) xe2x80x94(C3-C6)cycloalkyl, d) -phenyl or e) -benzyl.
In addition, more particularly, the present invention provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R1 is a) xe2x80x94(C1-C4)alkyl, b) xe2x80x94(C2-C4)alkenyl, c) -phenyl substituted with 0 or 1 of the following: xe2x80x94OH, xe2x80x94NR12R13, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C1-C4)alkyl, xe2x80x94CN, xe2x80x94Z-het, xe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, xe2x80x94NR12xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12xe2x80x94SO2xe2x80x94R13, xe2x80x94NR12xe2x80x94SO2-het, xe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C4)alkyl or xe2x80x94Oxe2x80x94SO2xe2x80x94(C1-C4)alkyl; d) xe2x80x94O-phenyl substituted with 0 or 1 of the following: xe2x80x94Zxe2x80x94NR12R13 or xe2x80x94C(O)NR12R13, or e) xe2x80x94CHxe2x95x90CH-phenyl wherein phenyl is substituted with 0 or 1 of the following: xe2x80x94Zxe2x80x94NR12R13 or xe2x80x94C(O)NR12R13;
Z for each occurrence is independently xe2x80x94(C0-C2)alkyl;
R10 is a) xe2x80x94CH(OH)(C1-C5)alkyl, b) xe2x80x94CN, c) xe2x80x94OH, d) -het, e) xe2x80x94C(O)xe2x80x94(C1-C4)alkyl, f) xe2x80x94C(O)xe2x80x94NR12R13, g) xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het, h) xe2x80x94Oxe2x80x94(C0-C2)alkyl-het, i) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, j) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-het or k) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-NR12R13;
R12 and R13 are independently a) xe2x80x94H or b) xe2x80x94(C1-C4)alkyl;
or R12 and R13 are taken together with N to form het.
Yet, even more particularly, the present invention provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R1 is a) xe2x80x94(C2-C4)alkyl, b) xe2x80x94CH2xe2x80x94CHxe2x95x90CH2 or c) -phenyl;
R2 is xe2x80x94OH;
R3 is a) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 CF3, b) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, c) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CF3, e) xe2x80x94CH2O(C1-C3)alkyl substituted with 0 or 1 CF3, or f) xe2x80x94CF3;
R10 is xe2x80x94OH.
Most particularly, the present invention provides:
compounds of formula III 
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs; wherein R3 and R10 are as defined immediately above.
In addition, the present invention more particularly provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R1 is a) xe2x80x94(C2-C4)alkyl, b) xe2x80x94CH2xe2x80x94CHxe2x95x90CH2 or c) -phenyl;
R2 is xe2x80x94OH;
R3 is a) xe2x80x94(C1-C5)alkyl substituted with 0 or 1 CF3, b) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, c) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CF3, e) xe2x80x94CH2O(C1-C3)alkyl substituted with 0 or 1 CF3, or f) xe2x80x94CF3; R10 is xe2x80x94CN.
Most particularly, the present invention provides:
compounds of formula III 
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs;
wherein R3 and R10 are as defined immediately above. Preferably, it provides a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94CN; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CH3 and R10 is xe2x80x94CN; a compound of formula III wherein R3 is xe2x80x94CF3 and R10 is xe2x80x94CN; and a compound of formula III wherein R3 is xe2x80x94CH2CH2CF3 and R10 is xe2x80x94CN; and pharmaceutically acceptable salts thereof.
In addition, the present invention more particularly provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R1 is a) xe2x80x94(C2-C4)alkyl, b) xe2x80x94CH2xe2x80x94CHxe2x95x90CH2 or c) -phenyl;
R2 is xe2x80x94OH;
R3 is a) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 CF3, b) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, c) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CF3, e) xe2x80x94CH2O(C1-C3)alkyl substituted with 0 or 1 CF3, or f) xe2x80x94CF3;
R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het wherein het is selected from the group consisting of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyl and e) oxadiazolyl;
Z is xe2x80x94(C0-C2) alkyl.
Most particularly, the present invention provides:
compounds of formula III 
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs; wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3;
R10 is as defined immediately above. Preferably, it provides a compound of formula III or a pharmaceutically acceptable salt thereof as follows: a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(4-pyridinyl); a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-pyridinyl); a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(3-pynidinyl); a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94(2-pyrazinyl); a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl); a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl); a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-pyridinyl); a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl); a compound of formula III wherein R3 is xe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl); a compound of formula III wherein R3 is xe2x80x94CH3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94(3-pyridinyl); and a compound of formula III wherein R3 is xe2x80x94CF3 and R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl).
In addition, the present invention more particularly provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R1 is a) xe2x80x94(C2-C4)alkyl, b) xe2x80x94CH2xe2x80x94CHxe2x95x90CH2 or c) -phenyl;
R2 is xe2x80x94OH;
R3 is a) xe2x80x94(C1-C4)alkyl substituted with 0 or 1 CF3, b) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, c) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CF3, e) xe2x80x94CH2O(C1-C3)alkyl substituted with 0 or 1 CF3, or f) xe2x80x94CF3;
R10 is xe2x80x94Oxe2x80x94(C1-C2)alkyl-het wherein het is selected from the group consisting of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyl and f) oxadiazolyl.
Most particularly, the present invention provides:
compounds of formula III 
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs;
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3;
R10 is xe2x80x94Oxe2x80x94(C1-C2)alkyl-het wherein het is selected from the group consisting of a) 2-pyridinyl, b) 3-pyridinyl, c) 4-pyridinyl, d) 2-methyl-3-pyridinyl and e) pyrazinyl. Preferably, it provides a compound of formula III and pharmaceutically acceptable salts thereof as follows: a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94CH2xe2x80x94(4-pyridinyl); a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94CH2xe2x80x94(2-pyridinyl); a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94Oxe2x80x94CH2xe2x80x94(3-pyridinyl); a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94Oxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl); a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94Oxe2x80x94CH2xe2x80x94(2-pyridinyl); and a compound of formula III wherein R3 is xe2x80x94CF3 and R10 is xe2x80x94Oxe2x80x94CH2xe2x80x94(2-methyl-3-pyridinyl).
In addition, the present invention more particularly provides:
compounds of formula II 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R1 is a) xe2x80x94(C2-C4)alkyl, b) xe2x80x94CH2xe2x80x94CHxe2x95x90CH2 or c) -phenyl;
R2 isxe2x80x94OH;
R3 is a) xe2x80x94(C1-C4)alkyl substituted with 0 or 1 CF3, b) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, c) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CF3, e) xe2x80x94CH2O (C1-C3)alkyl substituted with 0 or 1 CF3,or f) xe2x80x94CF3;
R10 is a) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-N((C1-C2)alkyl)2, b) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, or c) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-het wherein het is selected from the group consisting of 1) pyridinyl substituted with 0 or 1 methyl, 2) pyrimidinyl, 3) pyrazinyl, 4) morpholinyl, 5) pyrrolidinyl, 6) imidazolyl and 7) oxadiazolyl;
R12 and R13 are independently a) xe2x80x94H or b) xe2x80x94(C1-C2)alkyl; or R12 and R13 are taken together with N to form pyrrolidinyl;
Z is xe2x80x94(C0-C1) alkyl.
Most particularly, the present invention provides:
compounds of formula III 
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or prodrugs; wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3;
R10 is a) xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-N((C1-C2)alkyl)2, b) xe2x80x94Oxe2x80x94C(O)xe2x80x94N(CH3)2, c) xe2x80x94Oxe2x80x94C(O)xe2x80x94(1-pyrrolidinyl) or d) xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-het wherein het is selected from the group consisting of 1) 2-pyridinyl, 2) 3-pyridinyl, 3) 4-pyridinyl, 4) 2-methyl-3-pyridinyl, 5) pyrazinyl, 6) morpholinyl, 7) pyrrolidinyl and 8) imidazolyl. Preferably, it provides a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94(CH2)2xe2x80x94(1-pyrrolidinyl); a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94(CH2)2xe2x80x94N(CH3)2; a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94CH2-2-pyridyl; a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94CH2-4-pyridyl; and a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94CH2-3-pyridyl; and pharmaceutically acceptable salts of the above compounds.
The present invention also provides:
compounds of formula IV 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein the variables are as defined above for formula I.
More particularly, the present invention provides compounds of formula V, isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R8 is xe2x80x94H; R9 is xe2x80x94H on the C-ring; m is 2; R7 is xe2x80x94H; R14 is xe2x80x94H; R15 is xe2x80x94H; R16 is xe2x80x94H; and the A-ring is the moiety of formula A-1a.
Even more particularly, the present invention provides compounds of formula V 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein X is xe2x80x94CH2xe2x80x94;
R1 is a) xe2x80x94(C1-C4)alkyl, b) xe2x80x94(C2-C4)alkenyl, c) -phenyl substituted with 0 or 1 of the following: xe2x80x94OH, xe2x80x94NR12R13, xe2x80x94NR12xe2x80x94C(O)xe2x80x94(C1-C4)alkyl, xe2x80x94CN, xe2x80x94Z-het, xe2x80x94Oxe2x80x94(C1-C3)alkyl-C(O)xe2x80x94NR12R13, xe2x80x94NR12xe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, xe2x80x94Zxe2x80x94NR12xe2x80x94SO2xe2x80x94R13, xe2x80x94NR12xe2x80x94SO2-het, xe2x80x94Oxe2x80x94C(O)xe2x80x94(C1-C4)alkyl or xe2x80x94Oxe2x80x94SO2xe2x80x94(C1-C4)alkyl; d) xe2x80x94O-phenyl substituted with 0 or 1 of the following: xe2x80x94Zxe2x80x94NR12R13 or xe2x80x94C(O)NR12R13; or e) xe2x80x94CHxe2x95x90CH-phenyl wherein phenyl is substituted with 0 or 1 of the following: xe2x80x94Zxe2x80x94NR12R13 or xe2x80x94C(O)NR12R13;
Z is for each occurrence independently xe2x80x94(C0-C2)alkyl;
R4 and R5 are each hydrogen or are taken together to form xe2x95x90O;
R10 is a) xe2x80x94CH(OH)(C1-C5)alkyl, b) xe2x80x94CN, c) xe2x80x94OH, d) -het, e) xe2x80x94C(O)xe2x80x94(C1-C4)alkyl, f) xe2x80x94C(O)xe2x80x94NR12R13, g) xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het, h) xe2x80x94Oxe2x80x94(C0-C3)alkyl-het, i) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NR12R13, j) xe2x80x94Oxe2x80x94Zxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-het, or k) xe2x80x94Oxe2x80x94(C0-C3)alkyl-phenyl;
R12 and R13 for each occurrence are independently a) xe2x80x94H or b) xe2x80x94(C1-C4)alkyl.
Most particularly, the present invention provides compounds of formula VI 
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically acceptable salts of said compounds, isomers or prodrugs; wherein R2 is a) xe2x80x94C(O)OH, b) xe2x80x94C(O)OCH3, c) xe2x80x94C(O)OCH2CH3 or d) xe2x80x94CH2OH;
R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3 or d) xe2x80x94CF3;
R4 and R5 are each hydrogen or are taken together to form xe2x95x90O;
R10 is a) xe2x80x94OH, b) xe2x80x94Oxe2x80x94(C0-C3)alkyl-phenyl or c) xe2x80x94Oxe2x80x94(C0-C3)alkyl-het wherein het is selected from the group consisting of a) 2-pyridinyl, b) 3-pyridyl, c) 4-pyridyl, d) 2-methyl-3-pyridyl and e) pyrazinyl.
The present invention also provides:
compounds of formula VII 
and isomers thereof; wherein xe2x80x94is an optional bond;
Xxe2x80x2 is xe2x80x94CH2xe2x80x94;
Rxe2x80x21 is phenyl substituted with 0, 1 or 2 Rxe2x80x2x;
Rxe2x80x22 is xe2x80x94OH;
Rxe2x80x23 is a) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 Rxe2x80x2y or b) xe2x80x94(C2-C6)alkynyl substituted with 0 or 1 Rxe2x80x2y;
Rxe2x80x2y is xe2x80x94CF3;
or Rxe2x80x22 and Rxe2x80x23 are taken together to form xe2x95x90O;
Rxe2x80x29 is xe2x80x94H;
Rxe2x80x210 is a) -halo, b) xe2x80x94C(O)OH, c) xe2x80x94C(O)O(C1-C6)alkyl, d) xe2x80x94C(O)xe2x80x94NRxe2x80x212Rxe2x80x213, e) xe2x80x94CN, f) xe2x80x94OH or g) xe2x80x94Oxe2x80x94(C1-C3)alkyl;
Rxe2x80x2x is a) -halo, b) xe2x80x94OH, c) xe2x80x94(C1-C6)alkyl, d) xe2x80x94CN, e) xe2x80x94CF3, f) xe2x80x94(C0-C6)alkyl-NRxe2x80x22Rxe2x80x213, g) xe2x80x94C(O)xe2x80x94NRxe2x80x212Rxe2x80x213, h) xe2x80x94NRxe2x80x212xe2x80x94SO2Rxe2x80x213, i) xe2x80x94NRxe2x80x212xe2x80x94C(O)xe2x80x94Rxe2x80x213, j) xe2x80x94SO2Rxe2x80x212 or k) xe2x80x94SO2xe2x80x94NRxe2x80x212Rxe2x80x213;
Rxe2x80x212 and Rxe2x80x213 for each occurrence are each independently a) xe2x80x94H or b) xe2x80x94(C1-C6)alkyl. More particularly, the present invention provides the compound, 2(3H)-phenanthrenone, 4,4a,9,10-tetrahydro-7-bromo-4a-(phenylmethyl-,(S)xe2x80x94.
The present invention also provides:
compounds of formula VIII 
and isomers thereof;
wherein Dxe2x80x2 is C;
Xxe2x80x2 is xe2x80x94CH2xe2x80x94;
Rxe2x80x21 is phenyl substituted with 0 to 2 Rxe2x80x2x;
Rxe2x80x25, Rxe2x80x27, Rxe2x80x28, Rxe2x80x29, Rxe2x80x215 and Rxe2x80x216 for each occurrence are independently a) xe2x80x94H, b) xe2x80x94Oxe2x80x94(C1-C6)alkyl, c) xe2x80x94(C1-C6)alkyl or d) halo;
Rxe2x80x210 is a) -halo, b) xe2x80x94CN, c) xe2x80x94OH, d) xe2x80x94C(O)xe2x80x94NRxe2x80x212Rxe2x80x213, e) xe2x80x94C(O)xe2x80x94NRxe2x80x212xe2x80x94Zxe2x80x2-het wherein het is substituted with 0 or 1 Rxe2x80x2x, f)xe2x80x94C(O)xe2x80x94NRxe2x80x212xe2x80x94Zxe2x80x2-aryl wherein aryl is substituted with 0 or 1 Rxe2x80x2x, g) xe2x80x94Oxe2x80x94(C0-C6)alkyl-het wherein het is substituted with 0 or 1 Rxe2x80x2x, or h) xe2x80x94Oxe2x80x94(C0-C6)alkyl-aryl wherein aryl is substituted with 0 or 1 Rxe2x80x2x;
Zxe2x80x2 is a) xe2x80x94(C0-C6)alkyl, b) xe2x80x94(C2-C6)alkenyl, or c) xe2x80x94(C2-C6)alkynyl;
Rxe2x80x2x is a) -halo, b) xe2x80x94OH, c) xe2x80x94(C1-C6)alkyl, d) xe2x80x94CN, e) xe2x80x94CF3, f) xe2x80x94(C0-C6)alkyl-NRxe2x80x212Rxe2x80x213, g) xe2x80x94C(O)xe2x80x94NRxe2x80x212Rxe2x80x213, h) xe2x80x94NRxe2x80x212xe2x80x94SO2Rxe2x80x213, i) xe2x80x94NRxe2x80x212xe2x80x94C(O)xe2x80x94Rxe2x80x213, j) xe2x80x94SO2Rxe2x80x212 or k) xe2x80x94SO2xe2x80x94NRxe2x80x212Rxe2x80x213;
Rxe2x80x212 and Rxe2x80x213 for each occurrence are each independently a) xe2x80x94H or b) xe2x80x94(C1-C6)alkyl;
aryl is phenyl;
het is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. More particularly, the present invention provides the compound, 1(R)-benzyl-6-methoxy-1-(S)xe2x80x94(3-oxo-butyl)-3,4-dihydro-1H-naphthalen-2-one.
In addition, the present invention provides compounds of formula II 
an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein R1 is -phenyl;
R2 is xe2x80x94OH;
R3 is a) xe2x80x94(C1-C6)alkyl substituted with 0 or 1 CF3, b) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, c) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CF3, e) xe2x80x94CH2O(C1-C3)alkyl substituted with 0 or 1 CF3, or f) xe2x80x94CF3;
R10 is xe2x80x94OH, xe2x80x94CN, xe2x80x94C(O)OH or xe2x80x94C(O)O(C1-C6)alkyl.
More particularly, the present invention provides compounds of formula III 
a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug; wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; and
R10 is as defined immediately above. Most particularly, it provides a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94OH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94CN; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH3 and R10 is xe2x80x94COOH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CH3 and R10 is xe2x80x94OH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CH3 and R10 is xe2x80x94CN; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CH3 and R10 is xe2x80x94COOH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94OH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94CN; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94(CH2)2xe2x80x94CF3 and R10 is xe2x80x94COOH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94CH3 and R10 is xe2x80x94OH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94CH3 and R10 is xe2x80x94CN; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94CH3 and R10 is xe2x80x94COOH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94CF3 and R10 is xe2x80x94OH; or a pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is xe2x80x94CF3 and R10 is xe2x80x94CN; or a pharmaceutically acceptable salt thereof; and a compound of formula III wherein R3 is xe2x80x94CF3 and R10 is xe2x80x94COOH; or a pharmaceutically acceptable salt thereof.
The present invention provides methods of treating obesity in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. More particularly, the present invention provides such methods wherein the mammal is a female or male human.
The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
The present invention also provides pharmaceutical compositions for the treatment of obesity comprising an obesity treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
The present invention also provides pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising:
a first compound, said first compound being a compound of formula 1, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being a xcex23 agonist, a thyromimetic agent, an eating behavior modifying agent or a NPY antagonist; and
a pharmaceutical carrier, vehicle or diluent. More particularly, it provides such compositions wherein the second compound is orlistat or sibutramine.
In addition, the present invention provides methods of treating obesity comprising administering to a mammal in need of such treatment
an amount of a first compound, said first compound being a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being a xcex23 agonist, a thyromimetic agent, an eating behavior modifying agent or a NPY antagonist; and
wherein the amounts of the first and second compounds result in a therapeutic effect. More particularly, it provides such methods wherein the second compound is orlistat or sibutramine.
The present invention also provides kits comprising:
a) a first compound, said first compound being a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b) a second compound, said second compound being a xcex23 agonist, a thyromimetic agent, an eating behavior modifying agent or a NPY antagonist; and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c) a container for containing said first and second dosage forms; wherein the amounts of said first and second compounds result in a therapeutic effect.
In addition, the present invention provides methods of inducing weight loss in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. The present invention also provides pharmaceutical compositions for inducing weight loss comprising a weight loss-treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
Another aspect of the present invention provides methods of treating diabetes in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.
The present invention also provides pharmaceutical compositions for the treatment of diabetes comprising a diabetes-treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
In addition, the present invention provides pharmaceutical combination compositions comprising: a therapeutically effective amount of a composition comprising:
a first compound, said first compound being a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, insulin, troglitazone, sulfonylurea, glipizide, glyburide, or chlorpropamide; and
a pharmaceutical carrier, vehicle or diluent. More particularly, the present invention provides such pharmaceutical combinationcompositions wherein the aldose reductase inhbitior is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-or a pharmaceutically acceptable salt thereof.
The present invention also provides methods of treating diabetes comprising administering to a mammal in need of such treatment
an amount of a first compound, said first compound being a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, insulin, troglitazone, sulfonylurea, glipizide, glyburide, or chlorpropamide; and
wherein the amounts of the first and second compounds result in a therapeutic effect.
In another aspect, the present invention provides pharmaceutical combination compositions comprising:
therapeutically effective amounts of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and
a compound selected from the group consisting of a glucocorticoid receptor agonist, a cholinomimetic drug, an anti-Parkinson""s drug, an antianxiolytic drug, an antidepressant drug and an antipsychotic drug; and
a pharmaceutical carrier, vehicle or diluent. More particularly, it provides such compositions wherein the anti-Parkinson""s drug is selected from the group consisting of L-dopa, bromocriptine and selegiline. More particularly, it provides such compositions wherein the antianxiolytic drug is selected from the group consisting of benzodiazepine, valium and librium. More particularly, it provides such compositions wherein the antidepressant drug is selected from the group consisting of desipramine, sertraline hydrochloride and fluoxetine hydrochloride. More particularly, it provides such compositions wherein the antipsychotic drug is selected from the group consisting of haloperidol and clozapine.
The present invention also provides kits comprising:
a) a first compound, said first compound being a compound of formula I, an isomer thereof, a prodrug said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;
b) a second compound, said second compound being selected from the group consisting of a glucocorticoid receptor agonist; a cholinomimetic drug; an anti-Parkinson""s drug; an antianxiolytic drug; an antidepressant drug; and an antipsychotic drug; and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and
c) a container for containing said first and second dosage forms wherein the amounts of said first and second compounds result in a therapeutic effect. More particularly, it provides such kits wherein the anti-Parkinson""s drug is selected from the group consisting of L-dopa, bromocriptine and selegiline. More particularly, it provides such kits wherein the antianxiolytic drug is selected from the group consisting of benzodiazepine, valium and librium. More particularly, it provides such kits wherein the antidepressant drug is selected from the group consisting of desipramine, sertraline hydrochloride and fluoxetine hydrochloride. More particularly, it provides such kits wherein the antipsychotic drug is selected from the group consisting of haloperidol and clozapine.
In another aspect, the present invention provides methods of treating anxiety in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. It also provides pharmaceutical compositions for the treatment of anxiety comprising an anxiety-treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
In another aspect, the present invention provides methods of treating depression in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. It also provides pharmaceutical compositions for the treatment of depression comprising a depression-treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
In another aspect, the present invention provides methods of treating neurodegeneration in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. It also provides pharmaceutical compositions for the treatment of neurodegeneration comprising a neurodegeneration-treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or diluent.
In other aspects, the present invention provides the following methods: methods of affecting glucocorticoid receptor activity comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; methods of modulating a process mediated by glucocorticoid receptor comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; methods of treating a mammal requiring glucocorticoid receptor therapy comprising administering to said mammal a therapeutically effective amount of a glucocorticoid receptor modulator compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.
In another aspect, the present invention provides methods of treating an inflammatory disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. More particularly, it provides such methods wherein the mammal is a female or male human.
The present invention also provides pharmaceutical compositions for the treatment of an inflammatory disease comprising an inflammatory-treating amount of a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a pharmaceutically acceptable carrier.
In another aspect, the present invention provides methods for the treatment of an inflammatory disease in a mammal which comprises: administering to said mammal therapeutically effective amounts of a glucocorticoid receptor modulator and a glucocorticoid receptor agonist. More particularly, it provides such methods which further comprise reducing the undesirable side effects of said treatment. Also, it provides such methods wherein the inflammatory disease is selected from the group consisting of arthritis, asthma, rhinitis and immunomodulation. More particularly, it provides such methods wherein the glucocorticoid receptor modulator is a compound of formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug. Also, more particularly, it provides such methods wherein the glucocorticoid receptor agonist is a compound selected from the group consisting of prednisone, prednylidene, prednisolone, cortisone, dexamethasone and hydrocortisone.
The present invention also provides a process for preparing a compound of formula III 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; and R10 is xe2x80x94Oxe2x80x94CH2-het wherein het is pyridinyl substituted with 0 or 1 methyl;
which comprises reacting a compound of formula III-A 
wherein R3 is as defined above, with a base in an aprotic solvent at room temperature to 200xc2x0 C.; and then with a compound of formula R10xe2x80x94X1 wherein R10 is as defined above and xe2x80x94X1 is halo, mesylate or tosylate. More particularly, it provides this process wherein the base is NaH, t-butoxide or Et3N; and the solvent is DMF or THF.
The present invention also provides a process for the preparing a compound of formula III 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het wherein het is selected from the group consisting of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyl and e) oxadiazolyl; and Z is xe2x80x94(C0-C1) alkyl;
which comprises reacting a compound of formula III-B 
wherein R3 is as defined above, with a coupling reagent and a compound of formula NH2xe2x80x94Z-het or a salt thereof wherein xe2x80x94Z and -het are as defined above in an aprotic solvent at 0xc2x0 C. to 1000xc2x0 C. More particularly, it provides this process wherein the coupling reagent is selected from the group consisting of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt).
In addition, the present invention provides a process for preparing a compound of formula III 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het wherein het is selected from the group consisting of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, C) pyrazinyl, d) morpholinyl and e) oxadiazolyl; and Z is xe2x80x94(C0-C1) alkyl;
which comprises reacting a compound of formula III-C 
wherein R3 is as defined above, with a tri(C1-C4)alkyl-aluminum compound and a compound of formula NH2xe2x80x94Z-het wherein xe2x80x94Z and -het are as defined above in a solvent at 0xc2x0 C. to 40xc2x0 C. More particularly, it provides this process wherein the tri(C1-C4)alkyl-aluminum compound is Al(CH3)3 and the solvent is methylene chloride.
Further, the present invention provides a process for preparing a compound of formula III 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; R10 is a) xe2x80x94Oxe2x80x94C(O)xe2x80x94N(CH3)2, b) xe2x80x94O xe2x80x94C(O)xe2x80x94(1-pyrrolidinyl) or c) xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94(C0-C3)alkyl-het wherein het is selected from the group consisting of 1) 2-pyridinyl, 2) 3-pyridinyl, 3) 4-pyridinyl, 4) 2-methyl-3-pyridinyl, 5) pyrazinyl, 6) morpholinyl, 7) pyrrolidinyl and 8) imidazolyl;
which comprises reacting a compound of formula III-A 
wherein R3 is as defined above, with phosgene or triphosgene in an aprotic solvent and then with a compound selected from the group consisting of NH(CH3)2, 1-pyrrolidinyl and NH2xe2x80x94(C0-C3)alkyl-het wherein het is as defined above at 0xc2x0 C. to room temperature. More particularly, it provides this process wherein the solvent is toluene.
In addition, the present invention provides a process for preparing a compound of formula III 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; and R10 is xe2x80x94Oxe2x80x94(C1-C2)alkyl-het wherein het is pyridinyl substituted with 0 or 1 methyl;
which comprises reacting a compound of formula III-D 
wherein R10 is as defined above, with R3-metal selected from the group consisting of R3Li, R3MgBr and R3MgCl wherein R3 is as defined above in an aprotic solvent at xe2x88x9278xc2x0 C. to room temperature.
Further, the present invention provides a process for preparing a compound of formula III 
wherein R3 is xe2x80x94CF3; and R10 is xe2x80x94Oxe2x80x94(C1-C2)alkyl-het wherein het is pyridinyl substituted with 0 or 1 methyl;
which comprises a) reacting a compound of formula III-D 
wherein R10 is as defined above, with trimethylsilyl-CF3 in the presence of tert-butylammonium fluoride or cesium fluoride in a protic solvent; and b) hydrolyzing the resulting intermediate with tert-butylammonium fluoride or hydrochloric acid.
The present invention also provides process for preparing a compound of formula III 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het wherein het is selected from the group consisting of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyl and e) oxadiazolyl; and Z for each occurrence is independently xe2x80x94(C0-C2) alkyl;
which comprises reacting a compound of formula III-D 
wherein R10 is as defined above, with R3-metal selected from the group consisting of R3Li, R3MgBr and R3MgCl wherein R3 is as defined above in an aprotic solvent at xe2x88x9278xc2x0 C. to room temperature.
Finally, the present invention provides a process for preparing a compound of formula II 
wherein R3 is a) xe2x80x94(CH2)2xe2x80x94CF3, b) xe2x80x94(CH2)2xe2x80x94CH3, c) xe2x80x94CH3, d) xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, e) xe2x80x94Cxe2x89xa1Cxe2x80x94Cl or f) xe2x80x94CF3; R10 is xe2x80x94C(O)xe2x80x94NHxe2x80x94Z-het wherein het is selected from the group consisting of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyl and e) oxadiazolyl; and Z for each occurrence is independently xe2x80x94(C0-C2) alkyl;
which comprises a) reacting a compound of formula III-D 
wherein R10 is as defined above, with trimethylsilyl-CF3 in the presence of tert-butylammonium fluoride or cesium fluoride in a protic solvent; and b) hydrolyzing the resulting intermediate with tert-butylammonium fluoride or hydrochloric acid.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
In one way of naming the compounds of the present invention, the carbon atoms in the ring may be numbered as shown in the following simplified structure: 
Alternatively, another way of naming the compounds of the present invention, the carbon atoms in the ring may be numbered as shown in the following simplified structure: 
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-Cj indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-C3 alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, and all isomeric forms and straight and branched forms thereof.
Examples of alkyl of one to nine carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, and all isomeric forms and straight and branched thereof.
Examples of alkenyl of two to five carbon atoms, inclusive, are ethenyl, propenyl, butenyl, pentenyl, and all isomeric forms and straight and branched forms thereof.
Examples of alkynyl of two to five carbon atoms, inclusive, are ethynyl, propynyl, butynyl, pentynyl and all isomeric forms and straight and branched forms thereof.
The terms cycloalkyl, cycloalkenyl and cycloalkynyl refer to cyclic forms of alkyl, alkenyl and alkynyl, respectively. Exemplary (C3-C8)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term halo includes chloro, bromo, iodo and fluoro.
The term aryl refers to an optionally substituted six-membered aromatic ring, including polyaromatic rings. Examples of aryl include phenyl, naphthyl and biphenyl.
The term het refers to an optionally substituted 5-, 6- or 7-membered saturated, partially saturated or unsaturated heterocyclic ring containing from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic ring; and the nitrogen atom may be in the oxidized state giving the N-oxide form; and substituted by 0 to 3 independent substituents.
The following paragraphs describe exemplary ring(s) for the generic ring descriptions contained herein.
Exemplary five-membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizaolyl, 1,2,4-oxadiazolyi, 1,2,5-oxadiazolyi, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatrizaolyl, 3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl and 1,3-oxathiolyl.
Exemplary six-membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-trizainyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl.
Exemplary seven-membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.
Exemplary eight membered rings are cyclooctyl, cyclooctenyl and cyclooctadienyl.
Exemplary bicyclic rings consisting of combinations of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4Hquinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl.
As used herein the term xe2x80x9cmammalsxe2x80x9d is meant to refer to all mammals, including, for example, primates such as humans and monkeys. Examples of other mammals included herein are rabbits, dogs, cats, cattle, goats, sheep and horses.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, vehicle, diluent, excipient and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the Formula I compounds include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (C1-C4)alkyl, (C2-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,Nxe2x80x94(C1-C2)alkylamino(C2-C3)alkyl (such as xcex2-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
The compounds of formula I of the present invention are prepared as described in the Schemes, Preparations and Examples below, or are prepared by methods analogous thereto, which are readily known and available to one of ordinary skill in light of this disclosure. In each of the Schemes, the R groups (e.g., R1, R2, etc . . . ) correspond to those noted in the Summary above. In addition, the variable n is defined as 0 to 6. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of Formula I also comprise potential substituents for the analogous positions on the structures within the Schemes. 
The compound of formula A-1 (prepared as described in Org. Syn. 1971, 51, 109-112) (wherein D is methylene, substituted carbon, oxygen, sulfur or optionally protected nitrogen, R10 is halogen, hydrogen, methyl ether, or benzyl ether or is as described in the Summary above, and the other variables are as defined in the Summary above) is reacted with a nitrogen-containing base, such as pyrrolidine, piperidine or morpholine, at a refluxing temperature in an aprotic solvent such as toluene, benzene, dichloromethane or dioxane, and then reacted with the alkylating agent of formula R1Xxe2x80x94X1 wherein R1Xxe2x80x94is (C2-C4)alkyl straight chain or an isopropyl, t-butyl or benzyl group or is as described in the Summary above, and X1 is a leaving group (see Francis A. Carey, in Advanced Organic Chemistry, Part A, Chapter 5.6 for examples) in dioxane, methanol, ethanol, isopropanol, DMF, DMSO or THF to give the compound of formula A-2. Typical alkylating agents are primary, secondary, benzylic or allylic halides and are preferably alkyl bromides or alkyl iodides.
Alternatively, the compound of formula A-1 is converted to its anion with a strong base, such as sodium hydride, sodium methoxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium t-butoxide or others, in an aprotic solvent, such as dimethylformamide (DMF) or tetrahydrofuran (THF). This reaction is conducted at xe2x88x9278xc2x0 C. to room temperature depending on the nature of the base used. The resulting anion is alkylated with the appropriate alkylating agent of formula R1Xxe2x80x94X1 as defined previously to give the compound of formula A-2.
Alternatively, the compound of formula A-1 is reacted with R1Xxe2x80x94CHO and a base, such as pyrrolidine or an acid, such as acetic acid or hydrochloric acid, in a solvent such as toluene, benzene, methanol or ethanol. The intermediate thus obtained is then hydrogenated using a palladium on carbon catalyst or numerous other reagents such as platinum oxide or rhodium on aluminum oxide (see P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reactions, Chapter 1, pp. 1-45; and John Fried and John A. Edwards in Organic Reactions in Steroid Chemistry, Chapter 3, pp. 111-145) to give the compound of formula A-2. Alternatively, the intermediate is reacted with a reducing metal reagent, such as an alkali (group IA in the periodic table) or alkaline metal (group IIA in the periodic table), including Li, Na, or Ca, and an amine, such as NH3 or ethylene diamine, in an aprotic solvent, such as THF or dioxane, at xe2x88x9278xc2x0 C. to room temperature to give the compound of formula A-2.
The compound of formula A-2 is reacted with (R)-(+)-xcex1-methylbenzylamine (as shown in Scheme A-2) or (S)-(xe2x88x92)-xcex1-methylbenzylamine (as shown in Scheme A-1) and an electrophile of formula A-6 (to form a 6-membered ring) or an electrophile of formula A-7 (to form a 5-membered ring) wherein R5, R8 and R9 are as defined above in the Summary and X2 is a leaving group that is typically a halogen such as bromide (see Francis A. Carey, in Advanced Organic Chemistry, Part A, Chapter 5.6 for examples), in an aprotic solvent such as toluene to give the C2-S or C2-R substituted intermediates of formula A-2a (which will form a six-membered ring) and of formula A-2b (which will form a five-membered ring), as shown in Schemes A-1 and A-2. These intermediates of formula A-2a and A-2b may be ring closed or ring opened as illustrated in the schemes.
Alternatively, the compound of formula A-2 is reacted with an electrophile of formula A-6 (to form a 6-membered ring) or with an electrophile of formula A-7 (to form a 5-membered ring) and a base, such as sodium methoxide or KOH, in a solvent, such as methanol, to give a racemic mixture of the intermediates of formula A-2a of Schemes A-1 and A-2 (which will form a six-membered ring) or to give a racemic mixture of the intermediates of formula A-2b of Schemes A-1 and A-2 (which will form a five-membered ring). This reaction may also give directly a racemic mixture of the products A-3a of Schemes A-1 and A-2 (which have a six-membered ring) or give directly a racemic mixture of the products A-3b of Schemes A-1 and A-2 (which have a five-membered ring), which mixtures may be resolved by chiral HPLC or by other literature methods.
The resulting intermediate of formula A-2a or A-2b is reacted with a base, such as sodium methoxide or KOH, in a solvent, such as methanol, or is reacted with an acid such as p-toluenesulfonic acid in a solvent such as toluene to give the compound of formula A-3a or A-3b, respectively, wherein the variables are as defined in the Summary above and wherein R10 is halogen, hydrogen, methyl ether, or benzyl ether or is as described in the Summary above.
Alternatively, the compounds of formula A-3a or A-3b are prepared from the compound of formula A-2a or A-2b, respectively, by other reported, annulation methods, some of which are described in M. E. Jung, Tetrahedron, 1976, 32, pp. 3-31.
The compound of formula A-3a or A-3b wherein R10 is, for example, methoxy is reacted with BBr3 or BCl3 and tetrabutylammonium iodide or dimethylboron bromide in an aprotic solvent, such as dichloromethane or toluene at xe2x88x9278xc2x0 C. to room temperature to give the compound of formula A-3a or A-3b wherein R10 is, for example, hydroxy.
Alternatively, the compound of formula A-3a or A-3b wherein R10 is, for example, methoxy is reacted with sodium ethanethiol in DMF or is reacted with methionine in methanesulfonic acid to give the compound of formula A-3a or A-3b wherein R10 is, for example, hydroxy.
Also, the compound of formula A-3a or A-3b wherein R10 is, for example, hydroxy may be prepared by other literature methods as described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991) or as illustrated in Comprehesive Organic Transformation, R. C. Larock, VCH Publishers Inc. (1989), pp. 501-527.
The compound of formula A-3a or A-3b wherein R10 is halogen, hydrogen, methyl ether, or hydroxy or is as described in the Summary above is hydrogenated with a palladium on carbon catalyst or other reagents such as platinum oxide or rhodium on aluminum oxide (see P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reactions, Chapter 1, pp. 1-45; and John Fried and John A. Edwards in Organic Reactions in Steroid Chemistry, Chapter 3, pp. 111-145) in a variety of solvents including methanol, ethanol, and THF to yield the compound of formula A4a or A-4b or A-5a or A-5b wherein the variables are as described in the Summary above and wherein the cis compounds are the major products.
The compound of formula A-3a or A-3b wherein R10 is hydrogen, methyl ether, hydroxy or is as described in the Summary above is reacted with a reducing metal reagent, such as an alkali (group IA in the periodic table) or alkaline metal (group IIA in the periodic table), including Li, Na, or Ca, and an amine, such as NH3 or ethylene diamine, in an aprotic solvent, such as THF or dioxane, at xe2x88x9278xc2x0 C. to room temperature to give the compound of formula A-5a or A-5b or A-4a or A-4b wherein the variables are as described in the Summary above and wherein the trans compounds are the major products.
Alternatively, as shown in Scheme A-3, for example, the compound of formula A-3a or A-3b of Scheme A-1 wherein R10 is halogen, hydrogen, methyl ether, hydroxy, carboxyl or is as described in the Summary above is treated with an alcohol or diol, such as methanol or ethylene glycol, and a strong acid, such as p-toluenesulfonic acid, in an aprotic solvent, such as toluene or benzene, to form a ketal intermediate of formula A-6 wherein m is one or two, Ra is lower alkyl or wherein the Ra""s taken together with the two oxygen atoms form, for example, 1,3-dioxolane and wherein the other variables are as defined in the Summary above. Alternatively, this ketal intermediate may be prepared by other literature methods such as those described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991). The ketal intermediate is hydrogenated using Pd(OH)2 on carbon or other reagents, such as platinum oxide or rhodium on aluminum oxide (see P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reactions, Chapter 1, pp. 1-45; and John Fried and John A. Edwards in Organic Reactions in Steroid Chemistry, Chapter 3, pp. 111-145) in a solvent such as toluene from 15-2000 psi (which is about 1 to about 133 atm) H2 at room temperature to 100xc2x0 C. The resultant intermediate of formula A-7 is then reacted with an acid, such as p-toluenesulfonic acid, in acetone or is reacted using various literature methods, such as those described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991), to yield the compound of formula A-5a of Scheme A-1 or the compound of formula A5-b of Scheme A-1 wherein R10 is halogen, hydrogen, methyl ether, hydroxy or is as described in the Summary above, and the other variables are as defined in the Summary above. The corresponding stereoisomers of these compounds are prepared by procedures analogous to those described above.
Alternatively, as shown in Scheme A-3, for example, the compound of formula A-3a or A-3b of Scheme A-1, wherein R10 is halogen, hydrogen, methyl ether, hydroxy or is as described in the Summary above, is reacted with triethylorthoformate and p-toluenesulfonic acid in ethanol or toluene to form an enol ether intermediate of formula A-8 wherein m is one or two, Ra1 is ethyl or other acyclic or cyclic lower alkyl or acyl, depending on the reagent used, and the other variables are as defined in the Summary above. Alternatively, this enol ether intermediate may be prepared by other literature methods such as those described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991). The enol ether intermediate is then hydrogenated using Pd on CaCO3 or other reagents, such as platinum oxide or rhodium on aluminum oxide (see P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985, Herbert O. House in Modern Synthetic Reactions, Chapter 1 pp. 1-45, and John Fried and John A. Edwards in xe2x80x9cOrganic Reactions in Steroid Chemistry,xe2x80x9d Chapter 3 pp. 111-145) in a variety of solvents including ethanol, methanol, and THF at 15-60 psi H2 pressure. The resulting intermediate of formula A-9 is then reacted with an acid such as aqueous HCl, in a protic solvent, such as ethanol, or is reacted under other literature conditions, such as those described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991), to yield the compound of formula A-5a of Scheme A-1 (which has a six-membered ring) or the compound of formula A-5b of Scheme A-1 (which has a five-membered ring) wherein R10 is halogen, hydrogen, methyl ether, hydroxy or is as described in the Summary above, and the other variables are as defined in the Summary above. The corresponding stereoisomers of these compounds are prepared by procedures analogous to those described above.
Alternatively, the resulting intermediate of formula A-3a or A-3b of Scheme A-1 is hydrogenated using Pd/BaSO4 in a solvent such as ethanol at 15 to 200 psi H2 pressure to yield the compound of formula A-5a of Scheme A-1 (which has a six-membered ring) or the compound of formula A-5b of Scheme A-1 (which has a five-membered ring) wherein R5 is COORa2 and wherein Ra2 is, for example, C1-C6 alkyl. Other reagents which may be used in the above hydrogenation reactions are described in P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985.
Alternatively, in Schemes A-1 and A-2, the compounds of formula A-5a or A-5b are prepared from the compounds of formula A-3a or A-3b, respectively, by other reported reduction methods, some of which are described in P. Jankowski, S. Marczak, J. Wicha, Tetrahedron, 1998, 12071-12150.
The compound of formula B-1, which is obtained as described in Scheme A-1 and Scheme H, is reacted with a base, such as NaH, t-butoxide or Et3N, in an aprotic solvent, such as DMF or CH3CN, at a temperature which is between room temperature and 200xc2x0 C. depending on the nature of the solvent used, and is then reacted with an alkylating agent of formula Rbxe2x80x94X1 wherein X1 is a leaving group, to give the compound of formula of B-2 wherein Rb is, for example, alkyl or alkyl-heterocycle and is further illustrated by a variety of different groups within the definition of R10 in the Summary above. To obtain compounds of formula B-2 which are carbamates wherein Rb is, for example, xe2x80x94C(O)NR12R13 and wherein R12 and R13 are as defined in the Summary above, the compound of formula B-1 is reacted with a compound of formula R12R13xe2x80x94NC(O)Cl. Alternatively, to obtain compounds of formula B-2, which are carbamates wherein Rb is, for example, C(O)NR12R13, the compound of formula B-1 is reacted with phosgene or triphosgene in an aprotic solvent such as toluene and then with an amine of the formula R12R13NH. To obtain compounds of formula B-2 which are thiocarbamates wherein Rb is, for example, xe2x80x94C(S)NR12R13 and R12 and R13 are defined in the Summary above, the compound of formula B-1 is reacted with a compound of the formula R12R13NC(S)Cl. Throughout this scheme, the other variables are as defined in the Summary above.
The compound of formula B-3 wherein n is, for example, one to six (prepared by the procedures for the formula B-2 compound) is reacted with a base such as Na2CO3 with or without sodium iodide in an aprotic solvent, such as DMF, at a temperature which is between room temperature and 200xc2x0 C., depending on the nature of the solvent used, and is then reacted with an amine of formula R12R13NH to obtain the compound of formula B-4 wherein n is, for example one to six and R12 and R13 are as defined in the Summary above.
The compound of formula B-5 wherein n is, for example, one to six, (prepared by the procedures for the formula B-2 compound) is reacted with OsO4, N-methylmorpholine-N-oxide or K2MnO4 to give the corresponding diol. The diol is oxidatively cleaved with NalO4 or Pb(OAc)4 to give the compound of formula B-6 wherein n is one to six, for example. Alternatively, the compound of formula B-5 is reacted with ozone and quenched with dimethyl sulfite, triphenylphosphine or other known reagent to give the compound of formula B-6. Alternatively, the compound of formula B-6 is obtained from the compound of formula B-5 by the methods illustrated in Comprehensive Organic Transformation, R. C. Larock, VCH Publisher, Inc. (1989) pp. 595-596, pp. 615-616.
Alternatively, the compound of formula B-4 wherein n is, for example, one to six, and R12 and R13 are as defined in the Summary above, is obtained from the compound of formula B-6 wherein n is one to six, for example, by reductive amination. The reductive amination is typically carried out with a reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably at a pH of between 6 and 8. The reaction is normally performed in a protic solvent, such as methanol or ethanol, or in a mixture of solvents, such as dichloroethane/methanol, at temperature of about xe2x88x9278xc2x0 C. to about 40xc2x0 C. (See A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. Vol. 34, Issue 31, 5595-98, 1990). Other conditions involve the use of titanium isopropoxide and sodium cyanoborohydride (R. J. Mattson et al., J. Org. Chem. 1990, 55, 2552-4) or involve the formation of the imine under dehydrating conditions followed by reduction (Comprehensive Organic Transformation, R. C. Larock, VCH Publisher, Inc (1989) pp. 421-425).
The compound of formula B-7 wherein n is, for example, one to six (prepared by the procedures for the formula B-2 compound) is reacted with a hydroxyamine or its HCl salt in a protic solvent, such as ethanol or methanol, and a base such as K2CO3 at a temperature between room temperature and 150xc2x0 C., depending on the nature of the solvent used, to give the compound of formula B-8 wherein n is one to six, for example.
To obtain compounds of formula B-9 wherein, for example, Rb1 is alkyl, and n is one to six, the compound of formula B-8 wherein n is one to six, for example, is reacted with a base, such as NaH and Rb1xe2x80x94CH2CO2Et in an aprotic solvent such as THF at a temperature between room temperature to 140xc2x0 C., depending on the nature of the solvent used. To obtain compounds of formula B-9 wherein Rb1 is xe2x95x90O and n is, for example one to six, the compound of formula B-8 wherein n is one to six, for example, is reacted with a base, such as pyridine and 2-ethylhexylchloro-formate in an aprotic solvent, such as DMF. The intermediate thus obtained is refluxed in xylene or other high boiling point aromatic solvent to give the compound of formula B-9 wherein Rb1 is xe2x95x90O. To obtain compounds of formula B-9 wherein Rb1 is xe2x95x90S and n is, for example, one to six, the compound of formula B-8 wherein n is one to six, for example, is reacted with a base such as DBU in an aprotic solvent, such as CH3CN and TCDI (1,1-thiocarbonyidiimidazole).
The compound of formula B-7 wherein n is, for example, one to six, is reacted with TMSN3 and AlMe3 in an aprotic solvent such as toluene at between 40xc2x0 C. to 200xc2x0 C., depending on the nature of the solvent used, to give the compound of formula B-10 wherein n is one to six, for example. Alternatively, the compound of formula B-10 is obtained by reacting the above compound of formula B-7 with NaN3 and triethylamine or ammonium chloride in an aprotic solvent, such as DMF, at elevated temperatures.
The compound of formula B-7 wherein n is, for example, one to six, is reacted with an amine and Al(Me)3 in an aprotic solvent, such as toluene, at a temperature between room temperature and 180xc2x0 C., depending on the nature of the solvent used, to give the compound of formula B-11 wherein n is, for example, one to six and R12 and R13 are as defined in the Summary above. Alternatively, this compound of formula B-11 is obtained by reacting the above compound of formula B-7 with an amine in the presence of a Lewis acid, such as AlCl3 or ZnCl2 at 150xc2x0 C. to 200xc2x0 C., or in the presence of an organometallic reagent, such as CuCl, CuBr or lanthanide (III) triflate. (See Tetrahedron Lett. 1993, Vol. 34, Issue 40, 6395-6398.)
The compound of formula B-12 wherein n is, for example, one to six (prepared by the procedures for the formula B-2 compound) is reacted with an amine or its salt and Al(Me)3 in an aprotic solvent, such as dichloromethane, to give the compound of formula B-13 wherein n is, for example, one to six and R12 and R13 are independently hydrogen, alkyl, hydroxy or methoxy, for example or as defined in the Summary above. Alternatively, the compound of formula B-12 is hydrolyzed by the methods mentioned in Greene and Wuts, Protecting Groups in Organic Synthesis, Wiley, New York (1981) to give the corresponding free acid. The free acid thus obtained is reacted with an amine and a coupling reagent, such as DCC or EDCl, to give the above compound of formula B-13 (as illustrated in Comprehensive Organic Transformation, R. C. Larock, VCH Publisher, Inc. (1989) pp. 972-976).
To obtain compounds of formula B-14 wherein, for example, n is one to six, Z is O and Rb2 is alkyl or halo, the compound of formula B-12 wherein n is one to six, for example, is reacted with a base, such as NaH, in an aprotic solvent, such as THF, and NH2C(xe2x95x90Nxe2x80x94OH)Rb2 wherein R1 is alkyl at refluxing temperatures. To obtain compounds of formula B-14 wherein, for example, n is one to six, Z is N and Rb2 is alkyl or halo, the compound of formula B-12 wherein n is one to six, for example, is reacted with a base, such as NaOMe, in a protic solvent, such as MeOH, and aminoguanidine nitrate.
The compound of formula B-15 wherein R12 and R13 are as defined in the Summary above (prepared by the procedures for the formula B-2 compound) is dissolved in an aprotic solvent such as toluene and refluxed to give the compound of formula B-16 wherein R12 and R13 are as defined in the Summary above. 
The compound of formula C-1 (which is the same as the compound of formula B-1, see Scheme B) is treated with an acid scavenger, such as 2,6-lutidine, diisopropylethylamine, or potassium carbonate, with a trifluoromethylsulfonylation reagent, such as trifluoromethylsulfonic anhydride, N-phenyltrifluoromethane-sulfonamide, or 4-nitrophenyltrifluoromethanesulfonate, with or without a catalyst, such as 4-dimethylaminopyridine (DMAP), in a solvent, such as dichloromethane, DMF or methyl-2-pyrrolidinone (NMP), from xe2x88x9278xc2x0 C. to room temperature to obtain the compound of formula C-2 wherein R10 is xe2x80x94OS(O)2CF3. Throughout this scheme, the other variables are as defined in the Summary above. Alternatively, the above compounds of formula C-2 are prepared from the compound of formula C-1 by other reported fluoroalkylsulfonylation methods, some of which are described in K. Ritter, Synthesis, 1993, pp. 735-762.
The compound of formula C-2 wherein the group at the R10 position is xe2x80x94OS(O)2CF3 or a halogen is reacted with metalcyanide, preferably zinc(II)cyanide (Zn(CN)2), and with a palladium source, such as tetrakis(triphenylphosphine) palladium(O) (Pd(PPh3)4), palladium(II)acetate, or tris(dibenzylidenacetone) dipalladium(O), in a solvent such as N-methyl-2-pyrrolidinone (NMP), DMF or acetonitrile, at room temperature to 120xc2x0 C. to give the cyano-substituted compound of formula C-3.
To obtain the compound of formula C-4 wherein, for example, Het is tetrazolyl, the compound of formula C-3 is reacted with dibutyltin oxide (Bu2SnO) and trimethylsilylazide (TMSN3) in toluene from room temperature to reflux. Alternatively, the compounds of formula C-4 wherein, for example, Het is tetrazolyl are prepared from the compound of formula C-3 by other reported methods, some of which are described in S J. Wittenberger, Organic Preparations and Procedures Int. 1994, 26(5), pp. 499-531. Alternatively, the compound of formula C-4 wherein Het is, for example, 2-pyridyl or 3-pyridyl, is obtained by reacting the compound of formula C-2 with a heterocycle-metal, such as bromo-2-pyridyl zinc or diethyl-(3-pyridyl)borane, and a catalyst, such as Pd(PPh3)2Cl2, tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4), or palladium acetate, and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, in an organic solvent, such as THF, DMF, or NMP at room temperature to 150xc2x0 C., depending on the nature of the solvent used.
The compound of formula C-2 is reacted under CO 1-3 atm, with a catalyst such as palladium acetate (Pd(OAc)2) and 1,1xe2x80x2-bis(diphenylphospino)ferrocene (DPPF) or bis(diphenylphosphino)propane (DPPP), tetrakis(triphenylphosphine) palladium(O) (Pd(PPh3)4), or tris(dibenzylidenacetone) dipalladium(O), and a base, such as triethylamine or potassium carbonate, with an alcohol, such as methanol, ethanol, or benzyl alcohol, in a solvent, such as DMF, NMP, or DMSO, at room temperature to 150xc2x0 C., depending on the nature of the solvent used, to give the ester of formula C-5, wherein Rc is, for example, alkyl or aryl.
An aqueous base, such as KOH, in a solvent, such as THF, is added to a solution of the compound of formula C-5 in a solvent, such as THF. The resulting solution is stirred at room temperature to reflux to give the acid of formula C-6.
A solution of the compound of formula C-6, diphenylphosphoryl azide (DPPA), triethylamine, and an alcohol of the formula RcOH, such as t-butanol, is stirred at room temperature to reflux to give the carbamate of formula C-7, wherein, for example, Rc is t-butyl.
The compound of formula C-6 is treated with a coupling reagent, such as 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), with or without a catalyst, such as 4-dimethylaminopyridine (DMAP), and an amine, R12R13NH, in an aprotic solvent, such as dichloromethane or DMF, at 0xc2x0 C. to room temperature to give the amide of formula C-8 wherein R12 and R13 are defined in the Summary above. Also, the compounds of formula C-8 can be prepared from the compound of formula C-6 by other reported, coupling methods, such as those described in Comprehensive Organic Transformation, R. C. Larock, VCH Publishers Inc. (1989), p 972-988.
Alternatively, the ester of formula C-5 is added to a mixture of trimethylaluminum (Al(CH3)3) and R12R13NH, such as 1-(3-aminopropyl)imidazole, in a solvent, such as dichloromethane, dichloroethane (DCE), or toluene at 0xc2x0 C. to room temperature. The resulting mixture is stirred at room temperature to reflux to obtain the amide of formula C-8 wherein, for example, R12 is hydrogen and R13 is propyl-imidazol-1-yl, and are further defined in the Summary above.
The ester of formula C-5 is reacted with a reducing agent, such as sodium borohydride or diisobutylaluminum hydride, in an organic solvent, such as methanol, THF or hexane depending on the nature of the reducing agent used, at xe2x88x9278xc2x0 C. to room temperature, to obtain the alcohol of formula C-9 wherein Rc1 is H. To obtain other compounds of formula C-9, wherein, for example, Rc1 is methyl, the compound of formula C-5 is reacted with Rc1-metal, such as methylmagnesium bromide, in an organic solvent, such as THF or toluene, at xe2x88x9278xc2x0 C. to room temperature.
The carbamate of formula C-7, wherein Rc is, for example, t-butyl, is reacted with an acid, such as trifluoroacetic acid (TFA), in a solvent, such as dichloromethane, at xe2x88x9278xc2x0 C. to room temperature to give the amine of formula C-10. Also, the compound of formula C-10 may be prepared from the compound of formula C-7, wherein Rc is t-butyl, benzyl, or other protecting groups, by other literature methods, some of which are described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991).
To obtain the compound of formula C-11 wherein Rc2 is xe2x80x94OSO2-methyl, the compound of formula C-9 wherein Rc1 is hydrogen or alkyl is reacted with a methylsulfonating reagent, such as methanesulfonyl chloride (MsCl), and an acid scavenger, such as diisopropylethylamine, in an organic solvent, such as THF or toluene at xe2x88x9278xc2x0 C. to room temperature. To obtain the compound of formula C-11 wherein Rc2 is Cl, the compound of formula C-9 wherein Rc1 is hydrogen or alkyl is reacted with a chlorinating reagent, such as thionyl chloride, an acid scavenger, such as pyridine, in an organic solvent, such as methylene chloride, at xe2x88x9278xc2x0 C. to room temperature.
The amine of formula C-10 is reacted with an acylating reagent, such as CH3COCl and an acid scavenger, such as triethylamine or pyridine, in a solvent, such as methylene chloride or THF, at xe2x88x9278xc2x0 C. to room temperature to give the amide of formula C-12 wherein R12 is as defined in the Summary above.
The compound of formula C-13 (which is obtained from the compound of formula C-6 by reacting it with N,O-dimethylhydroxylamine hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt and DMAP) is reacted with Rc3-Metal, such as ethylmagnesium bromide, in a solvent, such as THF or toluene, at xe2x88x9278xc2x0 C. to room temperature to give the compound of formula C-14, wherein Rc3 is, for example, ethyl.
The compound of formula C-11 and an amination reagent, such as sodium azide, in a solvent, such as DMF, NMP, or DMSO, are stirred at room temperature to 150xc2x0 C., depending on the nature of the solvent used, to give the compound of formula C-15 wherein Rc1 is hydrogen or alkyl and Rc4 is N3. The resulting azide is treated with a reducing reagent, such as triphenylphosphine (PPh3), in a solvent or mixture of solvents, such as THF, methanol and water, at xe2x88x9220xc2x0 C. to reflux, to give the compound of formula C-15 wherein Rc4 is NH2.
The aldehyde of formula C-14 wherein Rc3 is hydrogen or the ketone of formula C-14 wherein Rc3 is alkyl is treated with a reducing agent such as sodium borohydride or diisobutylaluminum hydride, in an organic solvent, such as methanol, THF, or hexane depending on the nature of the reducing agent used, at xe2x88x9278xc2x0 C. to room temperature, to obtain the alcohol of formula C-16 wherein Rc3 is, for example, ethyl.
The amine of formula C-15 wherein Rc1 is hydrogen or alkyl and Rc4 is xe2x80x94NH2 is reacted with an acylating reagent, such as CH3COCl and an acid scavenger, such as triethylamine or pyridine, in a solvent, such as methylene chloride or THF, at xe2x88x9278xc2x0 C. to room temperature to give the amide of formula C-17 wherein R12 and R13 are as defined in the Summary above. 
The compound of formula D-1 is prepared from commercially available cyclohexane-1,3-dione by literature procedures described in Chem. Ber., 85, 1061 (1952); Org. Syn., Coll. Vol. V, page 486; and S. Ramachandran and M. S. Newman, Org. Syn. 41, 38 (1961). It is reacted with triethylorthoformate, p-toluenesulfonic acid and ethanol in toluene to obtain the dienol ether of formula D-2. Throughout this scheme, the other variables are as defined in the Summary above.
The compound of formula D-2 in ethanol or methanol is hydrogenated using 1 atm of H2 over Pd/CaCO3 or strontium carbonate to obtain the compound of formula D-3. The compound of formula D-3 is reacted with lithium diisopropylamide (prepared from diisopropylamine and n-butyllithium) and n-bromo-succinimide in THF to obtain the brominated compound of formula D-4. The compound of formula D-3 is reacted with ethyl formate in THF and potassium t-butoxide to obtain the carboxaldehyde of formula D-5.
The compound of formula D-4 is hydrolyzed with an aqueous acid, such as sulfuric acid, to obtain the compound of formula D-6. Likewise, once the compounds of formula D-8 and D-9 are obtained, as described below, they are hydrolyzed with aqueous acid to obtain the compounds of formula D-10 and D-11, respectively.
The compound of formula D-6 is reacted with thiourea in acetonitrile and then heated to reflux to obtain the amine-substituted thiazole compound of formula D-7. The carboxaldehyde of formula D-5 is reacted with hydrazine in ethanol/water to obtain the pyrazole compound of formula D-8. The carboxaldehyde compound of formula D-5 is reacted with a refluxing solution of sodium metal and guanidine sulfate in isopropyl alcohol to obtain the amino-substituted pyrimidine compound of formula D-9.
The compound of formula D-7 is reacted with an organometallic compound, R3-Metal, such as R3Li, R3MgBr or R3MgCl, (for example, lithio-2-chloroethyne), in an aprotic solvent such as THF at xe2x88x9278xc2x0 C. to room temperature to obtain the compound of formula D-12 wherein R2 and R3 are, for example, hydroxy and chloroethynyl, respectively, and are further defined in the Summary above. Likewise, the compounds of formula D-13 and D-14 are obtained from the compounds of formula D-10 and D-11, respectively, by analogous procedures. 
The compound of formula E-1 (which is the same as the compound of formula A-3a (see Scheme A) wherein R10 is methoxy and the other variables are as defined in the Summary above) is treated with a reducing metal reagent, such as an alkali (group IA in the periodic table) or alkaline metal (group IIA in the periodic table), including Li, Na, or Ca, an amine, such as NH3 or ethylene diamine, and a proton source, such as t-butyl alcohol or ethanol, in an aprotic solvent, such as THF or dioxane, at xe2x88x9278xc2x0 C. to room temperature to give the compound of formula E-2, wherein the variables are as described in the Summary above.
The compound of formula E-2 wherein the variables are as described in the Summary above is reacted with R3-Metal, such as R3Li, R3MgBr or R3MgCl, wherein R3 is, for example, alkynyl, in an aprotic solvent such as THF at low temperature to give the compound of formula of E-3 wherein the variables are as described in the Summary above.
The compound of formula E-3 is treated with an aqueous acid, such as HCl, acetic acid, or oxalic acid, in a solvent, such as THF or dioxane, at xe2x88x9220xc2x0 C. to reflux to give the compounds of formula E-4 and E-5 wherein the variables are as defined in the Summary above in various ratios depending on the nature of the aqueous acid and the solvent used. Also, the compounds of formula E4 and E-5 may be prepared by other literature methods as described in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991). 
The compound of formula F-1 (prepared as described in Schemes A, B, C, and H) wherein the variables are as described in the Summary above is treated with an oxidizing agent, such as osmium tetroxide in t-butanol, with or without an agent to regenerate the oxidizing agent, such as N-methylmorpholine-N-oxide, with or without a catalyst, such as pyridine, in a solvent, such as methylene chloride, at 0xc2x0 C. to room temperature to obtain the diol compound of formula F-2 wherein the variables are as described in the Summary above.
The compound of formula F-2 wherein the variables are as described in the Summary above is reacted with a carbonylation reagent, such as carbonyldiimidazole, diphosgene or phosgene, in a solvent, such as THF or methylene chloride, at 0xc2x0 C. to reflux to obtain the (2-oxo-1,3-dioxolan-4-yl)methyl compound of formula F-3 wherein all the variables are as described in the Summary above.
The diol compound of formula F-2 wherein the variables are as described in the Summary above is oxidatively cleaved with an oxidation reagent, such as sodium periodate (NalO4), with or without an acid scavenger, such as sodium bicarbonate, in a solvent, such as methylene chloride, at 0xc2x0 C. to room temperature to obtain the aldehyde of formula F-4 wherein the variables are as described in the Summary above.
Alternatively, the compound of formula F-1 wherein the variables are as described in the Summary above is treated concomitantly with an oxidation reagent, such as osmium tetroxide in t-butanol, and an oxidative cleavage reagent, such as sodium periodate (NaIO4), with or without an agent to regenerate the oxidizing agent, such as N-methylmorpholine-N-oxide, with or without a catalyst, such as pyridine, in a solvent mixture, such as dioxane and water, at 0xc2x0 C. to room temperature to obtain the aldehyde of formula F-4 wherein the variables are as described in the Summary above.
Alternatively, the compound of formula F-1 wherein the variables are as described in the Summary above is treated with ozone in a solvent, such as THF, at xe2x88x9278xc2x0 C. to 0xc2x0 C. followed by treatment with a reducing agent, such as dimethyl sulfide, at xe2x88x9278xc2x0 C. to room temperature to obtain the aldehyde of formula F-4 wherein the variables are as described in the Summary above.
The aldehyde of formula F-4 wherein the variables are as described in the Summary above is treated with an amine, (NHR12R13, for example, piperidine), with or without a drying agent, such as molecular sieves or magnesium sulfate, with a reducing agent, such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaCNBH3), in a solvent or a mixture of solvents, such as acetic acid and/or dichoromethane, at 0xc2x0 C. to room temperature to obtain the compound of formula F-5, wherein, for example, R12 and R13 taken together are piperidinyl and wherein the other variables are as described in the Summary above.
The oxime-containing compound of formula F-6 wherein R12 is hydroxy or alkoxy and wherein the other variables are as described in the Summary above, is prepared by reacting the formula F-4 compound wherein the variables are as described in the Summary above with hydroxylamine or an alkoxyamine or an HCl salt, with or without a base, such as KHCO3 or pyridine, in a solvent, such as methanol, ethanol or pyridine, at 0xc2x0 C. to reflux.
An olefination reagent, such as PO(OR1)2CH2R1, is treated with a base, such as lithium diisopropyl amine (LDA) or n-butyl lithium, and is reacted with the aldehyde of formula F4 wherein the variables are as described in the Summary above in a solvent, such as THF at xe2x88x9278xc2x0 C. to room temperature to obtain the alkenyl compound of formula F-7 wherein the variables are as described in the Summary above.
The aldehyde of formula F-4 wherein the variables are as described in the Summary above is treated with a reducing agent, such as diisobutylaluminum hydride (DiBAl) in hexane or sodium borohydride (NaBH4), in a solvent, such as THF or methanol, at xe2x88x9278xc2x0 C. to room temperature to obtain the alcohol of formula F-8 wherein the variables are as described in the Summary above.
The alkenyl compound of formula F-7 wherein the variables are as described in the Summary above is hydrogenated using hydrogen with a palladium on carbon catalyst or other reagents such as platinum oxide or rhodium on aluminum oxide (see P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reactions, Chapter 1, pp. 1-45; and John Fried and John A. Edwards in Organic Reactions in Steroid Chemistry, Chapter 3, pp. 111-145) in a variety of solvents including methanol, ethanol and THF to obtain the compound of formula F-9 wherein the variables are as described in the Summary above.
The alcohol of formula F-8 is coupled with RfArylOH, utilizing an azocarboxylate such as diethylazodicarboxylate (DEAD), a trialkyl phosphine such as triphenylphosphine (PPh3) in a solvent, such as methylene chloride, to obtain the compound of formula F-10 wherein Rf is formyl and other aromatic substituents as described in the Summary above and the other variables are as defined in the Summary above. Alternatively, formula F-10 compounds are prepared by reacting the compound of formula F-8 with p-toluenesulfonyl chloride. The resulting intermediate in DMF is reacted with an alkali metal salt of Rf-ArylOH to give the compound of formula F-10.
The ester of formula F-11 (prepared from the aldehyde of formula F-4 by an olefination procedure described above) wherein Rf1 is, for example, methyl, and the other variables are as described in the Summary above is reacted with an aqueous base, such as KOH, in a solvent, such as THF, and the resulting solution is heated and stirred at room temperature to reflux to obtain the acid of formula F-11 wherein Rf1 is hydrogen and all the additional variables are as described in the Summary above.
The compound of formula F-11 wherein Rf1, is hydrogen and the other variables are as described in the Summary above is treated with a coupling reagent, such as 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), with or without a catalyst, such as 4-dimethylaminopyridine (DMAP), and an amine (R12R13NH, such as pyrrolidine), in an aprotic solvent, such as dichloromethane or DMF, at 0xc2x0 C. to room temperature to obtain the compound of formula F-12 wherein, for example R12 and R13 taken together are pyrrolidinyl, and the other variables are as described in the Summary above. Also, the compounds of formula F-12 are prepared from the compounds of formula F-11 by other reported, coupling methods, some of which are described in Comprehensive Organic Transformation, R. C. Larock, VCH Publishers Inc. (1989), pp. 972-988.
The compound of formula F-13 wherein Rf2 is COORf3, wherein Rf3 is, for example, methyl, and wherein the other variables are as defined in the Summary above (prepared from the aldehyde of formula F-4 by an olefination procedure described above) is hydrolyzed with an aqueous base, such as KOH, in a solvent, such as THF, and the resulting solution is stirred at room temperature to reflux to give the compound of formula F-13 wherein Rf2 is COOH and the other variables are as described in the Summary above.
The compound of formula F-13 wherein Rf2 is COOH is treated with a coupling reagent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), with or without a catalyst, such as 4-dimethylaminopyridine (DMAP), and an amine (R12R13NH, such as pyrrolidine), in an aprotic solvent, such as dichloromethane or DMF, at 0xc2x0 C. to room temperature to obtain the compound of formula F-14 wherein, for example R12 and R13 taken together are pyrrolidinyl, Rxe2x80x2 and Rxe2x80x2 are taken together to form xe2x95x90O, and the other variables are as described in the Summary above. Also, the compounds of formula F-14 are prepared from the compounds of formula F-13 by other reported, coupling methods, some of which are described in Comprehensive Organic Transformation, R. C. Larock, VCH Publishers Inc. (1989), pp. 972-988.
The compound of formula F-13 wherein Rf2 is CHO and the other variables are as described in the Summary above (which is prepared analogously to the compound of formula F-7) is treated with an amine, (NHR12R13, for example, piperidine), with or without a drying agent, such as molecular sieves or magnesium sulfate, and with a reducing agent, such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaCNBH3), in a solvent or a mixture of solvents, such as acetic acid and/or dichoromethane, at 0xc2x0 C. to room temperature to obtain the compound of formula F-14, wherein, for example, R12 and R13 taken together with the nitrogen atom are piperidinyl, each Rxe2x80x2 is H, and wherein the other variables are as described in the Summary above.
The protected compound of formula F-13 wherein Rf2 is, for example, xe2x80x94CH2OTBDMS is prepared from the aldehyde of formula F-4 by Wittig coupling as described above. This compound is deprotected to the alcohol by using tetabutylammonium fluoride in a solvent, such as tetrahydrofuran. This alcohol wherein Rf2 is CH2OH is reacted with methanesulfonyl chloride, diisopropylethylamine and a primary or secondary amine, such as morpholine, to give the compound of formula F-14 wherein R12 and R13 taken together are, for example, morpholinyl, each Rxe2x80x2 is H and the other variables are as described in the Summary above.
The compound of formula F-10 wherein Rf is CHO and the other variables are as described in the Summary above (which is prepared as described above) is treated with an amine, (NHR12R13, for example, piperidine), with or without a drying agent, such as molecular sieves or magnesium sulfate, and with a reducing agent, such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride (NaCNBH3), in a solvent or a mixture of solvents, such as acetic acid and/or dichoromethane, at 0xc2x0 C. to room temperature to obtain the compound of formula F-15, wherein, for example, R12 and R13 taken together with N are piperidinyl, Rxe2x80x2 is H and the other variables are as described in the Summary above. The compounds of formula F-15, wherein Rxe2x80x2 and Rxe2x80x2 taken together to form xe2x95x900, may be prepared by procedures analogous to those described above. 
The compound of formula G-1 wherein Z is NH2 and the other variables areas defined in the Summary above (which is prepared according to the procedures in Schemes A and H) is reacted with an aldehyde or ketone such as R12C(O)R13 and with sodium triacetoxyborohydride (Na(OAc)3BH) or sodium cyanoborohydride (NaCNBH3) as reducing agents to give the reductive amination product of formula G-2 wherein Z1 is N and the other variables are as defined in the Summary above. Alternatively, the compound of formula G-2 is prepared from the compound of formula G-1 by other reductive amination methods known in the art, such as those disclosed for the preparation of the compound of formula B-4 in Scheme B above.
The compound of formula G-1 wherein Z. is NH2 or OH is reacted with a coupling reagent, such as 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), and a base, such as 4-dimethylaminopyridine (DMAP) or triethylamine, in an aprotic solvent, such as methylene chloride, and an acid to give the compound of formula G-3 wherein Z1 is O or NR12, Rg is for example, alkyl and the other variables are as defined in the Summary above. Alternatively, the compound of formula G-3 is obtained from the compound of formula G-1 by standard acylation, such as treating the compound of formula G-1 with a base, such as pyridine, and an acyl halide or acid anhydride in an aprotic solvent to give the compound of formula G-3.
The compound of formula G-4 wherein Z1 is O or NR12 and the other variables are as defined in the Summary above is obtained from the compound of formula G-1 according to the procedures described in Scheme B, such as the preparation of the carbamate of formula B-2 wherein Rb is xe2x80x94C(O)NR12R13. Alternatively, the compound of formula G-4 wherein Z1 is NHBoc is reacted with a base, such as n-BuLi, in an aprotic solvent and an amine to give the compound of formula G-4 wherein Z1 is NH.
The compound of the formula G-1 is reacted with the compound of formula Rg1SO2Cl and a base, such as triethylamine, in an aprotic solvent, such as THF, to give the compound of formula G-5 wherein Z1 is O or NR12, Rg1 is, for example, alkyl and the other variables are as defined in the Summary above.
The compound of formula G-1 wherein Z1 is xe2x80x94NH2 and the other variables are as defined in the Summary above is reacted with (Me2NCHxe2x95x90N)2 in an aprotic solvent such as toluene and with an acid, such as p-toluenesulfonic acid, to give the compound of formula G-6 wherein the variables are as defined in the Summary above. 
The compound of formula H-1 wherein the variables are as described in the Summary above (which is prepared by the procedures in Scheme A above) is reacted with reagents such as P(Rh2)3CH2R12 or PO(ORh2)2CH2R12 wherein Rh2 is lower alkyl or aryl and the other variables are as defined in the Summary above and a base such as lithium diisopropylamide (LDA) or sodium hydride (NaH) in an aprotic solvent, such as THF or DMF, to give the compound of formula H-2 wherein Z is CH, and R12 and the other variables are as defined in the Summary above.
The compound of formula H-1 is reacted with the compound of formula H2NOR12 or its hydrochloride salt in ethanol or methanol, with or without sodium acetate (NaOAc), at room temperature or at the refluxing temperature of the solvent, to give the compound of formula H-2 wherein Z is N, and R12 and the other variables are as defined in the Summary above.
The compound of formula H-1 is reacted with RhOH wherein Rh is, for example, lower alkyl or ethylene glycol, and an acid such as p-toluenesulfonic acid in an aprotic solvent such as toluene at reflux temperature under Dean-Stark trap to remove water to give the compound of the formula H-3 wherein Rh is, for example, lower alkyl or wherein Rh""S taken together with the two oxygen atoms form, for example, 1,3-dioxolane, and the other variables are as defined in the Summary above.
The compound of the formula H-2 wherein Z is CH, R12 is, for example, alkyl and the other variables are as defined in the Summary above is reacted with H2, and Pd/C or other reagents as described by P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985 in a solvent, such as methanol, to give the compound of formula H-4 wherein Z is CH, R12 is, for example, alkyl, and the other variables are as defined in the Summary above.
The compound of the formula H-2 wherein Z is N, R12 is, for example, alkyl and the other variables are as defined in the Summary above is reacted with hydrochloric acid in methanol and borane-trimethyl-amine complex (Me3N,BH3) or other reducing reagents to give the compound of formula H-4 wherein Z is NH, R12 is alkyl and the other variables are as defined in the Summary above.
Alternatively, the compound of formula H-4 is obtained from the compound of formula H-2 by other hydrogenation procedures which are known and available in the art.
The compound of formula H-1 is reacted with trimethylsulfonium iodide ((CH3)3S+lxe2x88x92) or trimethylsulfoxonium iodide ((CH3)3S+xe2x86x92Olxe2x88x92) and a base, such as potassium t-butoxide, in an aprotic solvent such as DMF to give the compound of formula H-5 wherein the variables are as defined in the Summary above. Alternatively, the compound of formula H-5 is obtained from the compound of formula H-1 by an analogous method to that illustrated in Comprehensive Organic Transformation, R. C. Larock, VCH Publishers Inc. (1989), pp. 468-470.
The compound of formula H-1 is reacted with R3-Metal, such as R3Li, R3MgBr or R3MgCl, wherein R3 is, for example, alkynyl or alkyl in an aprotic solvent such as THF at low temperature to give the compound of formula H-6 wherein R3 is alkynyl or alkyl and the other variables are as defined in the Summary above.
The compound of formula H-1 is reacted with TMSCF3 and TBAF as described in G. A. Olah et al., J. Am. Chem. Soc. (1989) 111, 393, to give the compound of formula H-6 wherein R3 is xe2x80x94CF3 and the other variables are as defined in the Summary above. Alternatively, the compound of formula H-1 is treated with other xe2x80x94CF3 nucleophiles which are known and available in the literature including, but not limited to, that disclosed by J. Russell, N. Roques, Tetrahedron, 1998, 54, 13771-13782.
Alternatively, the compound of formula H-5, wherein the variables are as defined in the Summary above, is reacted with R3-Metal such as R3Li, R3MgBr, or R3MgCl wherein R3 is, for example, alkyl in an aprotic solvent such as THF at low temperature to give the compound of formula H-6 wherein R3 is, for example, xe2x80x94CH2-alkyl, and the other variables are as defined in the Summary above. Alternatively, the compound of formula H-5 wherein the variables are as defined in the Summary above is reacted with R3xe2x80x94X-Metal, such as R3ONa, R3SNa, R3OK, R3OLi or R3SLi wherein R3 is, for example, alkynyl and X is O or S in an aprotic solvent such as THF, at room temperature to the refluxing temperature of the solvent used, to give the compound of the formula H-6 wherein R3 is, for example, xe2x80x94Oxe2x80x94CH2-alkynyl or xe2x80x94Sxe2x80x94CH2-alkynyl and the other variables are as defined in the Summary above. Alternatively, the compound of formula H-5 wherein the variables are as defined in the Summary above is reacted with an amine in an aprotic solvent such as THF, at room temperature to the refluxing temperature of the solvent used, to give the compound of the formula H-6 wherein R3 is xe2x80x94CH2xe2x80x94NR12R13 and the other variables are as defined in the Summary above.
The compound of formula H-6 wherein R3 is alkynyl and the other variables are as defined in the Summary above is reacted with H2, Pd/C, or PtO2 to give the corresponding saturated alkyl product. The compound of formula H-6 wherein R3 is alkynyl and the other variables are as defined in the Summary above is reacted with LiAlH4 in an aprotic solvent such as THF to give the corresponding trans-alkenyl product. The compound of formula H-6 wherein R3 is alkynyl and the other variables are defined in the Summary above is reacted with H2 and Lindlar catalyst to give the corresponding cis-alkenyl product. Alternatively, these compounds are obtained using other conditions as described in Modern Synthetic Reactions, Herbert O. House, Ed., Chapters 1 and 2.
The compound of formula H-6 wherein R3 is hydroxyalkyl and the other variables are as defined in the Summary above is reacted with an acid such as p-toluenesulfonic acid in an aprotic solvent such as toluene at reflux temperature to give the compound of formula H-7 wherein n is 1 or 2 and the other variables are as defined in the Summary above. Alternatively, the compound of formula H-6 wherein R3 contains a leaving group such as halogen, mesylate, tosylate or triflate and the other variables are as defined in the Summary above is reacted with a base such as NaH in an aprotic solvent such as THF to give the compound with the formula H-7 wherein n is 1 or 2 and the other variables are as defined in the Summary above.
The compound of formula H-6 wherein the variables are as defined in the Summary above is reacted with a base such as Et3N or NaH and Rh1X wherein, for example, Rh1 is methyl and X is halogen or other leaving group in an aprotic solvent such as THF or methylene chloride to give the compound of formula H-8 wherein, for example, Rh1 is methyl and the other variables are as defined in the Summary above. Alternatively, the compound of formula H-6 wherein the variables are as defined in the Summary above is reacted with N2CHRh1, wherein, for example, Rh1 is methyl, and Rh(OAc)3, in an aprotic solvent such as methylene chloride to give the compound of formula H-8 wherein, for example, Rh1 is methyl and the other variables are as defined in the Summary above. 
The compound of formula I-1 wherein Ri is, for example, benzyl, and wherein m is one, is prepared as described in L. M. Fuentes, G. L. Larson, Tetrahedron Lett. 1982, 23 (3), pp. 271-274. The compound of formula I-1 wherein Ri is, for example, benzyl, and wherein m is two, is prepared as described in A. Ijima, K. Takashi, Chem Pharm. Bull. 1973, 21(1), pp. 215-219. The compound of formula I-1 and the compound of formula I-2 (which is commercially available) (or a salt of the compound of formula I-2, such as the hydrobromide or hydrochloride salt) are reacted in a solvent, such as isopropanol, at between 200xc2x0 C. and 300xc2x0 C. to obtain the compound of formula I-3 wherein R10 is hydroxy and the other variables are as described in the Summary above.
The compound of formula I-3 wherein R10 is hydroxy and the other variables are as described in the Summary above, which is in a solvent, such as DMF, is reacted with a base, such as potassium t-butoxide in t-butanol, and an electrophile, such as benzyl bromide, at 0xc2x0 C. to 100xc2x0 C. to obtain the compound of formula I-3 wherein R10 is, for example, xe2x80x94O-benzyl.
The compound of formula I-3 wherein R10 is, for example, xe2x80x94O-benzyl, and the other variables are as defined in the Summary above, which is in a solvent, such as THF, is treated with 2 eq. of a strong base, such as lithium diisopropylamide in THF, at xe2x88x9278xc2x0 C. to 0xc2x0 C., and is then treated with an electrophile, such as methylchloroformate (CICOOMe), at xe2x88x92780xc2x0 to 0xc2x0 C. A second electrophile, such as propyl iodide, is added and the resulting mixture heated to between 0xc2x0 C. to 55xc2x0 C. to give the compound of formula I-4 wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl, Ri1 is methoxy and the other variables are as defined in the Summary above.
The compound of formula I-4 wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl, Ri1 is methoxy and the other variables are as defined in the Summary above is hydrogenated to obtain the compound of formula I-4 wherein, for example, R10 is hydroxy, R3 is propyl, Ri1 is methoxy and the other variables are as defined in the Summary above, using ammonium formate(NH4+HCOOxe2x80x94) in methanol and a palladium on carbon catalyst at refluxing temperatures. The compound of formula I-5, which is prepared below, wherein, for example, R10 is xe2x80x94O-benzyl or xe2x80x94O-methyl, R3 is propyl and the other variables are as defined in the Summary above, is treated with boron tribromide (BBr3) in methylene chloride at xe2x88x9278xc2x0 C. to room temperature to obtain the corresponding compound wherein R10 is hydroxy. Likewise, the compound of formula I-6, which is prepared below, wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl and the other variables are as defined above, is cleaved under similar conditions. A variety of other hydrogenating agents and conditions are known and available in the art, such as using H2 on a palladium on carbon catalyst in methanol.
The compound of formula I-4 wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl, R11 is methoxy and the other variables are as defined in the Summary above, is reacted with a reducing agent, such as lithium aluminum hydride (LiAlH4), in a solvent, such as THF, at 0xc2x0 C. to refluxing temperatures to obtain the compound of formula I-5 wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl and the other variables are as defined in the Summary above.
The compound of formula I-4 wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl, Ri1 is methoxy and the other variables are as defined in the Summary above, is reacted with a reducing agent, such as lithium borohydride (LiBH4), in a solvent, such as THF, at 0xc2x0 C. to room temperature to obtain the compound of formula I-6 wherein, for example, R10 is xe2x80x94O-benzyl, R3 is propyl and the other variables are as defined in the Summary above. A variety of other esterifying conditions are known and available in the art.
The compound of formula I-7 (which is prepared by procedures described in Scheme A) is reacted with thallium trinitrite.3H2O in a solvent, such as methylene chloride to obtain the acid of formula I-8 wherein Ri2 is H and wherein, for example, R1xe2x80x94Xxe2x80x94is benzyl and R10 is CH3xe2x80x94C(O)xe2x80x94Oxe2x80x94, and wherein these variables are further defined in the Summary above.
The acid of formula I-8 wherein Ri2 is H and wherein, for example, R1xe2x80x94Xxe2x80x94is benzyl and R10 is CH3xe2x80x94C(O)xe2x80x94Oxe2x80x94, and wherein these variables are further defined in the Summary above, is reacted with an alcohol, such as methanol, and catalytic acid, such as sulfuric acid, at 0xc2x0 C. to reflux to obtain the ester of formula I-8 wherein Ri2 is methyl and wherein, for example, R1xe2x80x94Xxe2x80x94is benzyl and R10 is hydroxy, and wherein these variables are further defined in the Summary above. 
The compound of formula J-1 wherein the variables correspond to those in the Summary above (see scheme A for its preparation) is reacted with a base such as sodium methoxide, in a protic solvent such as methanol, and methyl acrylate to give the compound of formula of J-2 wherein the variables correspond to those in the Summary above. Alternatively, the compound of formula of J-1 is prepared using the conditions described in Scheme A for the preparation of the compound of formula A-2 from the compound of formula A-1.
The compound of formula of J-2 wherein the variables correspond to those in the Summary above is reacted with a base such as sodium carbonate in a protic solvent or mixed solvents such as methanol/water at 90xc2x0 C. to yield the compound of formula J-3 wherein the variables correspond to those in the Summary above. Alternatively, the compound of formula J-2 is hydrolyzed by the methods mentioned in Protecting Groups in Organic Synthesis, Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991) to give the corresponding free acid of formula J-3 wherein the variables correspond with those in the Summary above.
The compound of formula J-3 wherein the variables correspond with those in the Summary above is reacted with a reducing agent, such as sodium borohydride in a protic solvent such as ethanol to give the compound of the formula J-4 wherein the variables are as defined in the Summary above. Alternatively, the compound of the formula J-4 is prepared from the compound of formula J-3 according to other F reducing methods described in Modern Synthetic Reactions, Chapters 2-3, pp. 45-227, Herbert O. House, ed., Academic Press, New York (1985).
The compound of formula J-5 wherein the variables are as defined in the Summary above is prepared from the compound of formula J-4 using BBr3 or BCl3 and tetrabutylammonium iodide or dimethylboron bromide in an aprotic solvent, such as dichloromethane or toluene, at xe2x88x9278xc2x0 C. to room temperature.
The compound of formula J-6 is prepared from the compound of J-5 using the conditions described in Scheme H for the preparation of the compound of formula H-6 from the compound of formula H-1.
All compounds in this Scheme can serve as intermediates for Schemes A-3, B, C, F, G, or H.
The compound of formula K-1 (prepared as described in Scheme A-3), wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a hydroboration reagent, such as BH3 in THF, in an aprotic solvent, such as THF or dioxane, from 0xc2x0 C. to 60xc2x0 C. and then treated with an oxidizing agent, such as hydrogen peroxide and aqueous sodium hydroxide, from 0xc2x0 C. to 60xc2x0 C. to give the compound of formula K-2. Alternatively, the compound of formula K-2 is prepared from the compound of formula K-1 by other methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 497-498.
The compound of formula K-2, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, RK is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such as diglyme, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound in formula K-5. Alternatively, the compound of formula K-5 is prepared from the compound of formula K-2 by other halogenation methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 353-363.
The compound of formula K-2, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with an oxidizing agent, such as (nPr)3NRuO4 and N-methylmorpholine-N-oxide, in a solvent, such as dichloromethane, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound in formula K-3. Alternatively, the compound of formula K-3 is prepared from the compound of formula K-2 by other oxidation methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 604-614.
The compound of formula K-3, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such as diglyme, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound in formula K-6. Alternatively, the compound of formula K-6 is prepared from the compound of formula K-3 by other halogenation methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 353-363.
The compound of formula K-1, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with an oxidizing agent capable of allylic oxidation, such as selenium dioxide (SeO2) and/or t-butyl hydrogen peroxide or chromium trioxide, in a solvent, such as dichloromethane, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound of formula K-4. Alternatively, the compound of formula K4 is prepared from the compound of formula K-2 by other oxidation methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 592-593.
The compound of formula K-4, wherein Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and the other variables are as described in the Summary above, is reduced using Pd(OH)2 on carbon or other reagents, such as platinum oxide or rhodium on aluminum oxide (see P. N. Rylander in Hydrogenation Methods, Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reactions, Chapter 1, pp. 1-45; and John Fried and John A. Edwards in Organic Reactions in Steroid Chemistry, Chapter 3, pp. 111-145) under 15 to 1000 p.s.i (which is about 1 to about 133 atm) H2 pressure in a solvent, such as toluene, t-butyl methyl ether, or ethanol, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound in formula K-7.
The compound of formula K-7, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a reducing agent, such as sodium borohydride or lithium aluminum hydride, in a solvent, such as methanol or THF, from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of the reductant and/or solvent used, to give the compound in formula K-9, wherein R7 is hydrogen. Alternatively, the compound of formula K-9 is prepared from the compound of formula K-4 by other reduction methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 527-547. Alternatively, the compound of formula K-7, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether, or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with R7-metal, such as R7Li, R7MgBr, or R7MgCl, wherein R7 is, for example, alkyl, in an aprotic solvent, such as THF or diethyl ether from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of R7-metal and/or solvent used, to give the compound in formula K-9, wherein R7 is, for example, alkyl.
The compound of formula K-3, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a reducing agent, such as sodium borohydride or lithium aluminum hydride, in a solvent, such as methanol or THF, from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of the reductant and/or solvent used, to give the compound in formula K-8, wherein R15 is hydrogen. Alternatively, the compound of formula K-8 is prepared from the compound of formula K-3 by other reduction methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 527-547. Alternatively, the compound of formula K-3, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with R15-metal, such as R15Li, R15MgBr, or R15MgCl, wherein R15 is, for example, alkyl, in an aprotic solvent, such as THF or diethyl ether from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of R15-metal and/or solvent used, to give the compound in formula K-8, wherein R15 is, for example, alkyl.
The compound of formula K-7, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are lower alkyl, and all other variables are as described in the Summary above, is converted to its anion with a base, such as sodium hydride, sodium methoxide, or lithium diisopropylamide, in a solvent, such as THF or DMF from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of the base and solvent used. The reaction mixture is treated with an alkylating agent of formula R14-X, wherein R14 is, for example, alkyl and X is a leaving group (see Francis A. Carey, in Advanced Organic Chemistry, Part A, Chapter 5.6 for examples) to give the compound of formula K-10, wherein R14 and R15 are, for example, alkyl or hydrogen or mixtures thereof.
The compound of formula K-3, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is converted to its anion with a base, such as sodium hydride, sodium methoxide, or lithium diisopropylamide, in a solvent, such as THF or DMF from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of the base and solvent used. The reaction mixture is treated with an alkylating agent of formula R7-X, wherein R7 is, for example, alkyl and X is a leaving group (see Francis A. Carey, in Advanced Organic Chemistry, Part A, Chapter 5.6 for examples) to give the compound of formula K-11, wherein R7 and R16 are, for example, alkyl or hydrogen or mixtures thereof.
The compound of formula K-10, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a reducing agent, such as sodium borohydride or lithium aluminum hydride, in a solvent, such as methanol or THF, from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of the reductant and/or solvent used, to give the compound of formula K-12, wherein R7 is hydrogen. Alternatively, the compound of formula K-12 is prepared from the compound of formula K-10 by other reduction methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 527-547. Alternatively, the compound of formula K-10, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with R7-metal, such as R7Li, R7MgBr, or R7MgCl, wherein R7 is, for example, alkyl, in an aprotic solvent, such as THF or diethyl ether from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of R7-metal and/or solvent used, to give the compound of formula K-12, wherein R7 is, for example, alkyl.
The compound of formula K-11, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a reducing agent, such as sodium borohydride or lithium aluminum hydride, in a solvent, such as methanol or THF, from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of the reductant and/or solvent used, to give the compound of formula K-13, wherein R15 is hydrogen. Alternatively, the compound of formula K-13 is prepared from the compound of formula K-11 by other reduction methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 527-547. Alternatively, the compound of formula K-11, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with R15-metal, such as R15Li, R15MgBr, or R15MgCl, wherein R15 is, for example, alkyl, in an aprotic solvent, such as THF or diethyl ether from xe2x88x9278xc2x0 C. to 60xc2x0 C., depending on the nature of R15-metal and/or solvent used, to give the compound of formula K-13, wherein R15 is, for example, alkyl.
The compound of formula K-7, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such as diglyme, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound in formula K-14. Alternatively, the compound of formula K-14 is prepared from the compound of formula K-7 by other halogenation methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 353-363.
The compound of formula K-9, wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for example, lower alkyl or wherein Rk""s taken together are cyclic lower alkyl, and all other variables are as described in the Summary above, is treated with a fluorinating agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such as diglyme, from 0xc2x0 C. to 60xc2x0 C., depending on the nature of the solvent used, to give the compound in formula K-15. Alternatively, the compound of formula K-15 is prepared from the compound of formula K-9 by other halogenation methods known in the art, as exemplified in Comprehensive Organic Transformations, R. C. Larock, VCH Publishers Inc. (1989), pp. 353-363.
Some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl in Formula I precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1991.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds and of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Any of the compounds and prodrugs of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, sulfonic, citric, camphoric, maleic, acetic, lactic, nicotinic, nitric, succinic, phosphoric, malonic, malic, salicyclic, phenylacetic, stearic, palmitic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, fumaric, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, p-toluenesulfonic, naphthalenesulfonic, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts would be apparent to one of ordinary skill in the art. Where more than one basic moiety exists, the expression includes multiple salts (e.g., di-salt).
Some of the compounds of this invention are acidic and they form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and they form a salt with a pharmaceutically acceptable anion. All such salts, including di-salts, are within the scope of this invention and they can be prepared by conventional methods. They can be prepared simply by contacting the acidic and basic entities, in either an aqueous, non-aqueous or partially aqueous medium. For example, the mesylate salt is prepared by reacting the free base form of the compound of Formula I with methanesulfonic acid under standard conditions. Likewise, the hydrochloride salt is prepared by reacting the free base form of the compound of Formula I with hydrochloric acid under standard conditions. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
In addition, when the compounds and prodrugs of the present invention form hydrates or solvates, they are also within the scope of the present invention.
The compounds and prodrugs of the present invention also includes racemates, stereoisomers and mixtures of these compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.
For instance, the compounds of the present invention have asymmetric carbon atoms and are therefore enantiomers or diastereomers. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical/chemical differences by methods known in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diasteromeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof are considered as part of this invention.
The following configurations of the compounds of the present invention (as represented by simplified structures) are preferred, with the first configuration being more preferred: 
Also, the compounds and prodrugs of the present invention can exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof. All such tautomeric forms are included within the scope of the present invention.
The GR agonists, partial agonists and antagonists of the present invention can be used to influence the basic, life sustaining systems of the body, including carbohydrate, protein and lipid metabolism, electrolyte and water balance, and the functions of the cardiovascular, kidney, central nervous, immune, skeletal muscle and other organ and tissue systems. In this regard, GR modulators are used for the treatment of diseases associated with an excess or a deficiency of glucocorticoids in the body. As such, they may be used to treat the following: obesity, diabetes, cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration (for example, Alzheimer""s and Parkinson""s), cognition enhancement, Cushing""s Syndrome, Addison""s Disease, osteoporosis, frailty, inflammatory diseases (such as osteoarthritis, rheumatoid arthritis, asthma and rhinitis), tests of adrenal function, viral infection, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing, compulsive behavior, multi-drug resistance, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, medical catabolism and prevention of muscle frailty.
The compounds of the present invention, isomers, prodrugs and pharmaceutically acceptable salts thereof are useful to induce weight loss in mammals needing or desiring to lose weight. While not intending to limit the present invention to a specific mechanism of action, the compounds of the present invention, isomers, prodrugs and salts thereof are able to induce weight loss by a variety of mechanisms, such as appetite suppression, decreasing food intake, and stimulation of the metabolic rate in peripheral tissue, thereby increasing energy expenditure. In addition, the compounds of the present invention, isomers, prodrugs and salts thereof are useful to induce a more favorable partitioning of nutrients from fat to muscle tissue in mammals. Thus, while not necessarily resulting in weight loss, this increase in muscle mass may be useful in preventing or treating diseases, such as obesity and frailty.
In addition, the compounds of the present invention, isomers, prodrugs and pharmaceutically acceptable salts thereof may also be useful to increase lean meat deposition, improve lean meat to fat ratio, and trim unwanted fat from non-human animals, as described further below.
It will be understood by those skilled in the art that while the compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of the present invention will typically be employed as selective agonists, partial agonists or antagonists, there may be instances where a compound with a mixed steroid receptor profile is preferred.
Furthermore, it will be understood by those skilled in the art that the compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of the present invention, including pharmaceutical compositions and formulations containing these compounds, isomers, prodrugs and salts can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of the present invention can be used in conjunction with other pharmaceutical agents for the treatment of the disease/conditions described herein. For example, they may be used in combination with pharmaceutical agents that treat obesity, diabetes, inflammatory disease, immunodefficiency, hypertension, cardiovascular disease, viral infection, HIV, Alzheimers""s disease, Parkinson""s disease, anxiety, depression, or psychosis. In combination therapy treatment, both the compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods.
For instance, glucocorticoid receptor agonists are efficacious agents for the treatment of various inflammatory diseases; however, treatment is often accompanied by undesirable side effects. These side effects include, but are not limited to, the following examples: metabolic effects, weight gain, muscle wasting, decalcification of the skeleton, osteoporosis, thinning of the skin and thinning of the skeleton. However, according to the present invention, glucocorticoid receptor modulators may be used in combination with glucocorticoid receptor agonists to block some of these side effects, without inhibiting the efficacy of the treatment. Thus, any glucocorticoid receptor agonist may be used as the second compound in the combination aspect of the present invention. This combination includes the treatment of various inflammatory diseases, such as arthritis (osteo and rheumatiod), asthma, rhinitis, or immunomodulation. Examples of glucocorticoid receptor modulators include those known in the art (many of which are described above) as well as the novel compounds of formula I of the present invention. More particularly, examples of glucocorticoid receptor modulators known in the art include, but are not limited to, certain nonsteroidal compounds, such as 5H-chromeno[3,4-f]quinolines, which are selective modulators of steroid receptors, as disclosed in U.S. Pat. No. 5,696,127; and certain steroid compounds substituted at position 10, which possess antiglucocorticoid activity, and some of which have glucocorticoid activity, as disclosed in Published European Patent Application 0 188 396, published Jul. 23, 1986. Examples of glucocorticoid receptor agonists include those known in the art, such as prednisone (17,21-dihydroxypregnane-1,4-diene-3,11,20-trione), prednylidene ((11xcex2)-11,17,21-trihydroxy-16-methylenepregna-1,4-diene-3, 20-dione), prednisolone ((11xcex2)-11,17,21-trihydroxypregna-1,4-diene-3, 20-dione), cortisone (17xcex1,21-dihydroxy-4-pregnene-3,11,20-trione), dexamethasone ((11xcex2, 16xcex1)-9-fluoro-11, 17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), and hydrocortisone (11xcex2, 17xcex1,21-trihydroxypregn-4-ene-3, 20-dione). These compounds, which are glucocorticoid receptor agonists, will generally be administered in the form of a dosage unit at a therapeutically effective amount of such compound. For example, prednisone or an equivalent drug may be administered from about 5 to about 80 mg, depending on the condition; hydrocortisone may be administered from about 100 to about 400 mg, depending on the condition; and dexamethasone may be administered from about 4 to about 16 mg, depending on the condition. These doses are typically administered once to twice daily, and for maintenance purposes, sometimes on alternate days.
For the treatment of Alzheimer""s disease, any cholinomimetic drug, such as donepizil, may be used as the second compound in the combination aspect of this invention.
For the treatment of Parkinson""s disease, any anti-Parkinson""s drug, such as L-dopa, bromocriptine, or selegiline, may be used as the second compound in the combination aspect of this invention.
For the treatment of anxiety, any antianxiolytic drug, such as benzodiazepine, valium, or librium, may be used as the second compound in the combination aspect of this invention.
For the treatment of depression, any tricyclic antidepressant such as, desipramine, or any selective serotonin reuptake inhibitor (SSRI""s), such as sertraline hydrochloride and fluoxetine hydrochloride, may be used as the second compound in the combination aspect of this invention.
For the treatment of psychosis, any typical or atypical antipsychotic drug, such as haloperidol or clozapine may be used as the second compound in the combination aspect of this invention.
Any aldose reductase inhibitor may be used as the second compound in the combination aspect of this invention. The term aldose reductase inhibitor refers to a compound which inhibits the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose reductase. Such inhibition is readily determined by those skilled in the art according to standard assays (J. Malone, Diabetes, 29:861-864, 1980, xe2x80x9cRed Cell Sorbitol, an Indicator of Diabetic Controlxe2x80x9d). A variety of aldose reductase inhibitors are described and referenced below; however other aldose reductase inhibitors will be known to those skilled in the art. Examples of aldose reductase inhibitors useful in the compositions and methods of this invention include, for example, zopolrestat, and other such compounds as disclosed and described in PCT/IB99/00206, filed Feb. 5, 1999 (the disclosure of which is hereby incorporated by reference), and assigned to the assignee hereof.
Any glycogen phosphorylase inhibitor may be used as the second compound in the combination aspect of this invention. The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards or eliminates the enzymatic action of glycogen phosphorylase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a glycogen macromolecule and inorganic phosphate to glucose-1-phosphate and a glycogen macromolecule which is one glucosyl residue shorter than the original glycogen macromolecule (forward direction of glycogenolysis). Such actions are readily determined by those skilled in the art according to standard assays (e.g., as described in PCT/IB99/00206, filed Feb. 5, 1999). A variety of these compounds are described in the following published international patent applications: WO 96/39384, published Dec. 12, 1996, and WO 96/39385, published Dec. 12, 1996; and in the following filed international patent application: PCT/IB99/00206, filed Feb. 5, 1999; the disclosures of all of these applications are hereby incorporated by reference herein.
Any sorbitol dehydrogenase inhibitor may be used as the second compound in the combination aspect of this invention. The term sorbitol dehydrogenase inhibitor refers to a compound which inhibits the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose. Such inhibition is readily determined by those skilled in the art according to standard assays (as described in U.S. Pat. No. 5,728,704 and references cited therein). A variety of these compounds are described and referenced below; however other sorbitol dehydrogenase inhibitors will be known to those skilled in the art. U.S. Pat. No. 5,728,704 (the disclosure of which is hereby incorporated by reference) discloses substituted pyrimidines which inhibit sorbitol dehydrogenase, lower fructose levels, and/or treat or prevent diabetic complications, such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy and diabetic macroangiopathy.
Any known, commercially marketed antidiabetic compound may be used as the second compound in the combination aspect of this invention. A variety of such compounds are described and referenced below; however other such compounds will be known to those skilled in the art. Examples of such compounds useful in the compositions and methods of this invention include, for example, insulin, metformin, troglitazone (REZULIN(copyright)) and sulfonylureas, such as glipizide (GLUCOTROL(copyright)), glyburide (GLYNASE(copyright), MICRONASE(copyright)) and chlorpropamide (DIABINASE(copyright)).
Any xcex2-adrenergic agonist may be used as the second compound in the combination aspect of this invention. xcex2-Adrenergic agents have been categorized into xcex21, xcex22, and xcex23 subtypes. Agonists of xcex2-receptors promote the activation of adenyl cyclase. Activation of xcex21 receptors invokes increases in heart rate. Activation of xcex22 receptors induces relaxation of smooth muscle tissue which produces a drop in blood pressure and the onset of skeletal muscle tremors. Activation of xcex23 receptors is known to stimulate lipolysis, which is the breakdown of adipose tissue triglycerides to glycerol and fatty acids. Activation of xcex23 receptors also stimulates the metabolic rate, thereby increasing energy expenditure. Accordingly, activation of xcex23 receptors promotes the loss of fat mass. Compounds that stimulate xcex2 receptors are therefore useful as anti-obesity agents. Compounds which are xcex23-receptors agonists have hypoglycemic and/or anti-diabetic activity. Such activity is readily determined by those skilled in the art according to standard assays (International Patent Application, Publication No. WO 96/35671). Several compounds are described and referenced below; however, other xcex2-adrenergic agonists will be known to those skilled in the art. International Patent Application, Publication No. WO 96/35671 (the disclosure of which is incorporated herein by reference) discloses compounds, such as substituted aminopyridines, which are xcex2-adrenergic agonists. International Patent Application, Publication No. 93/16189 (the disclosure of which is incorporated herein by reference) discloses the use of selective xcex23 receptor agonists in combination with compounds which modify eating behavior for the treatment of obestiy.
Any thyromimetic antiobesity agent may be used as the second compound in the combination aspect of this invention. These compounds are tissue selective thyroid hormone agonists. These compounds are able to induce weight loss by mechanisms other than appetite suppression, e.g., through stimulation of the metabolic rate in peripheral tissue, which, in turn, produces weight loss. Such metabolic effect is readily measured by those skilled in the art according to standard assays. A variety of these compounds are described and referenced below; however other thyromimetic antiobesity agents will be known to those skilled in the art. It is well known to one of ordinary skill in the art that selectivity of thermogenic effect is an important requirement for a useful therapeutic agent in the treatment of, for example, obesity and related conditions.
Any eating behavior modifying compound may be used as the second compound of this invention. Compounds which modify eating behavior include anorectic agents, which are compounds which diminish the appetite. Such classes of anorectic agents are well known to one of ordinary skill in the art. A variety of these compounds are described in and referenced below; however, other anorectic agents will be known to those skilled in the art. Also, the following are antiobesity agents: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a Neuropeptide Y (hereinafter also referred to as xe2x80x9cNPYxe2x80x9d) antagonist, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotoninergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as xe2x80x9cleptinxe2x80x9d), a leptin analog, a galanin antagonist or a Gl lipase inhibitor or decreaser (such as orlistat). Other antiobesity agents include phosphatase 1B inhibitors, bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor modulators, orexin receptor antagonists, urocortin binding protein antagonists or glucagon-like peptide-1 (insulinotropin) agonists. A particularly preferred monoamine reuptake inhibitor is sibutramine, which can be prepared as disclosed in U.S. Pat. No. 4,929,629, the disclosure of which is incorporated herein by reference. Preferred serotoninergic agents include fenfluramine and dexfenfluramine, which can be prepared as disclosed in U.S. Pat. No. 3,198,834, the disclosure of which is incorporated herein by reference. A particularly preferred dopamine agonist is bromocriptine, which can be prepared as disclosed in U.S. Pat. Nos. 3,752,814 and 3,752,888, the disclosures of which are incorporated herein by reference. Another preferred anorectic agent is phentermine, which can be prepared as disclosed in U.S. Pat. No. 2,408,345, the disclosure of which is incorporated herein by reference.
Any NPY receptor antagonist may be used as the second component in the combination aspect of this invention. The term NPY receptor antagonist refers to compounds which interact with NPY receptors and inhibit the activity of neuropeptide Y at those receptors and thus are useful in treating disorders associated with neuropeptide Y, such as feeding disorders, including obesity. Such inhibition is readily determined by those skilled in the art according to standard assays (such as those described in International Patent Application, Publication No. WO 99/07703). In addition, the compounds described and referenced below are NPY receptor antagonists; however, other NPY receptor antagonists will also be known to those skilled in the art. International Patent Application, Publication No. WO 99/07703 (the disclosure of which is hereby incorporated by reference) discloses certain 4-aminopyrrole (3,2-d) pyrimidines as neuropeptide Y receptor antagonists. International patent application, Publication No. WO 96/14307, published May 17, 1996; International patent application, Publication No. WO 96/40660, published Dec. 19, 1996; International patent application, Publication No. WO 98/03492; International patent application, Publication No. WO 98/03494; International patent application, Publication No. WO 98/03493; International patent application, Publication No. WO 96/14307, published May 17, 1996; International patent application, Publication No. WO 96/40660, published Dec. 19, 1996; (the disclosures of which are hereby incorporated by reference) disclose additional compounds, such as substituted benzylamine derivatives, which are useful as neuropeptide Y specific ligands.
In combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to mammals (e.g., humans, male or female) by conventional methods. As recognized by those skilled in the art, the therapeutically effective amounts of the compounds of this invention and the other drug therapies to be administered to a patient in combination therapy treatment will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
For example, the second compound of this invention, when administered to a mammal, is dosed at a range between about 0.01 to about 50 mg/kg/day body weight, preferably about 0.1 mg/kg/day to about 10 mg/kg/day body weight, administered singly or as a divided dose. Particularly, when the second compound of this invention is (1) sibutramine, the dosage of sibutramine is about 0.01 mg/kg/day to about 30 mg/kg/day body weight, preferably about 0.1 mg/kg/day to about 1 mg/kg/day body weight; (2) dexfenfluramine, the dosage of dexfenfluramine is about 0.01 mg/kg/day to about 30 mg/kg/day body weight, preferably about 0.1 mg/kg/day to about 1 mg/kg/day body weight; (3) bromocriptine, the dosage of bromocriptine is about 0.01 to about 10 mg/kg/day body weight, preferably 0.1 mg/kg/day to about 10 mg/kg/day body weight; (4) phentermine, the dosage of phentermine is about 0.01 mg/kg/day to about 10 mg/kg/day, preferably about 0.1 mg/kg/day to about 1 mg/kg/day body weight. Also, for example, as noted above, an amount of an aldose reductase inhibitor that is effective for the activities of this invention may be used as the second compound of this invention. Typically, an effective dosage for aldose reductase inhibitors for this invention is in the range of about 0.1 mg/kg/day to about 100 mg/kg/day in single or divided doses, preferably about 0.1 mg/kg/day to about 20 mg/kg/day in single or divided doses.
As noted above, the compounds, isomers, prodrugs and pharmaceutically acceptable salts of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier, vehicle or diluent to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human, patients. The particular carrier, vehicle or diluent employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, for example, intravenous, oral, topical, suppository or parenteral. Also, the compounds, isomers, prodrugs and salts thereof of this invention can be administered individually or together in any conventional dosage form, such as an oral, parenteral, rectal or transdermal dosage form.
For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablefting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds, prodrugs and pharmaceutically acceptable salts thereof of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.
For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).
The pharmaceutical compositions and compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of the present invention will generally be administered in the form of a dosage unit (e.g., tablet, capsule, etc.) at a therapeutically effective amount of such compound, prodrug or salt thereof from about 0.1 xcexcg/kg of body weight to about 500 mg/kg of body weight, more particularly from about 1 xcexcg/kg to about 250 mg/kg, and most particularly from about 2 xcexcg/kg to about 100 mg/kg. More preferably, a compound of the present invention will be administered at an amount of about 0.1 mg/kg to about 500 mg/kg of body weight, and most preferably from about 0.1 mg/kg to about 50 mg/kg of body weight. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
Since the present invention has an aspect that relates to the treatment of the disease/conditions described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of formula I, an isomer thereof, a prodrug thereof or a salt of such compound, isomer or prodrug and a second compound as described above. The kit comprises a container, such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of formula I compound (or an isomer, prodrug or pharmaceutically acceptable salt thereof) can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The following paragraphs describe exemplary formulations, dosages etc. useful for non-human animals. The administration of compounds of this invention can be effected orally or non-orally, for example by injection. An amount of a compound of formula I, an isomer, prodrug or pharmaceutically acceptable salt thereof, is administered such that a therapeutically effective dose is received, generally a daily dose which, when administered orally to an animal is usually between 0.01 and 500 mg/kg of body weight, preferably between 0.1 and 50 mg/kg of body weight. Conveniently, the medication can be carried in the drinking water so that a therapeutic dosage of the agent is ingested with the daily water supply. The agent can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water soluble salt). Conveniently, the active ingredient can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate. A premix or concentrate of therapeutic agent in a carrier is more commonly employed for the inclusion of the agent in the feed. Suitable carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds. A particularly effective carrier is the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the active materials in the finished feed with which the premix is blended. It is important that the compound be thoroughly blended into the premix and, subsequently, the feed. In this respect, the agent may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier. It will be appreciated that the proportions of active material in the concentrate are capable of wide variation since the amount of agent in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of therapeutic agent.
High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound according to the invention. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.
If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.
The present invention has several advantagous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and trim unwanted fat from pet animals, the present invention provides the means by which this can be accomplished. For poultry and swine raisers, using the method of the present invention yields leaner animals which command higher prices from the meat industry.
Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the invention with a sufficient amount of animal feed to provide from about 10xe2x88x923 to 500 ppm of the compound in the feed or water.
The preferred medicated swine, cattle, sheep and goat feed generally contain from 1 to 400 grams of active ingredient per ton of feed, the optimum amount for these animals usually being about 50 to 300 grams per ton of feed.
The preferred feed of domestic pets, such as cats and dogs, usually contain about 1 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of feed.
For parenteral administration in animals, the compounds of the present invention may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean mean to fat ratio is sought.
In general, parenteral administration involves injection of a sufficient amount of a compound of the present invention to provide the animal with 0.01 to 500 mg/kg/day of body weight of the active ingredient. The preferred dosage for poultry, swine, cattle, sheep, goats and domestic pets is in the range of from 0.1 to 50 mg/kg/day of body weight of active ingredient.
Paste formulations can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an effective amount of a compound of the present invention can be prepared by admixing a compound of the present invention with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, can be added to improve the pelleting process.
It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has been found that implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal""s body.
The activity of the compounds of the present invention are demonstrated by one or more of the assays described below:
The following is a description of an assay for the identification of glucocorticoid receptor antagonists/agonists: HeLa cells containing endogenous human glucocorticoid receptors are transfected with a 3xGRE-luciferase plasmid generated by standard procedures and a plasmid conferring neomycin resistance. Novel glucocorticoid responsive cell lines are generated and characterized. One such cell line designated HeLa-GRE9 is used for determining the activity of compounds at the glucocorticoid receptor. Cells are maintained in charcoal-stripped serum and transferred to 96-well microtiter plates one day prior to treatment with various concentrations (10xe2x88x9212 to 10xe2x88x925) of test compounds in the absence and presence of known glucocorticoid receptor agonists (i.e., dexamethasone, hydrocortisone) for up to 24 hours. Treatments are performed in triplicate. Cell lysates are prepared and luciferase activity is determined using a luminometer. Agonist activity is assessed by comparing the luciferase activity from cells treated with test compound to cells treated with the agonist dexamethasone. Antagonist activity is assessed by comparing the luciferase activity of an EC50 concentration of dexamethasone in the absence and presence of test compound. The EC50 (concentration that produced 50% of the maximal response) for dexamethasone is calculated from dose response curves.
The following is a description of an assay for determining the competitive inhibition binding of the Human Type II Glucocorticoid receptor expressed in Sf9 cells:
Binding protocol: Compounds are tested in a binding displacement assay using human glucocorticoid receptor expressed in Sf9 cells with 3H-dexamethasone as the ligand. Human glucorticoid receptor is expressed in Sf9 cells as described in Mol. Endocrinology 4:209, 1990. Pellets containing Sf9 cells expressing the human GR receptor from 1L vats are lysed with 40 ul of 20 mM AEBSF stock (Calbiochem, LaJolla, Calif.) containing 50 mg/ml leupeptin and 40 ml of homogenization buffer is added. The assay is carried out in 96-well polypropylene plates in a final volume of 130 ul containing 200 ug Sf9 lysate protein, 6.9 nM 3H-dexamethasone (Amersham, Arlington Heights, Ill.) in presence of test compounds, test compound vehicle (for total counts) or excess dexamethasone (7 uM non-radioactive, to determine non-specific binding) in an appropriate volume of assay buffer. All compounds are tested at 6 concentrations in duplicate (concentration range 0.1-30 nM or 3-1000 nM). Test compounds are diluted from a 25 mM stock in 100% DMSO with 70%EtOH and added in a volume of 2 xcexcl. Once all additions are made the plates are shaken, sealed with sealing tape and incubated at 4xc2x0 C. overnight.
After the overnight incubation, unbound counts are removed with dextran coated charcoal as follows: 75 xcexcl of dextran coated charcoal (5.0 g activated charcoal, 0.5 g dextran adjusted to volume of 100 ml with assay buffer) is added, plates are shaken and incubated for five minutes at 4xc2x0 C. Plates are then centrifuged in a refrigerated benchtop centrifuge at top speed for 15 minutes. 100 xcexcl of the supernatant from each well is placed into a 96-well PET plate with 200 xcexcl of scintillation cocktail and counted on a beta counter (1450 MicroBetaTrilux, from Wallac, Turku, Finland).
Data analysis: After subtracting non-specific binding, counts bound are expressed as % of total counts. The concentration response for test compounds are fitted to a sigmoidal curve to determine the IC50 (concentration of compound that displaces 50% of the bound counts).
Reagents: Assay Buffer: 2.0 ml 1M Tris, 0.2 ml 0.5 mM EDTA, 77.1 mg DTT, 0.243 g sodium molybdate in a volume of 100 ml water; Homogenization buffer: 2.0 ml 0.5M K2HPO4 (pH 7.6), 20 xcexcl 0.5M EDTA (pH 8.0), 77.1 mg DTT, 0.486 g sodium molybdate in a volume of 100 ml water.
The following is a description of an assay for determining receptor selectivity: T47D cells from ATCC containing endogenous human progesterone and mineralocorticoid receptors are transiently transfected with a 3xGRE-luciferase using Lipofectamine Plus (GIBCO-DRL, Gaithersburg, Md.). Twenty-four hours post-transfection cells are maintained in charcoal-stripped serum and transferred to 96-well microtiter plates. The next day cells are treated with various concentrations (10xe2x88x9212 to 10xe2x88x925) of test compounds in the absence and presence of a known progesterone receptor agonist (progesterone) and a known mineralocorticoid receptor agonist (aldosterone) for up to 24 hours. Treatments are performed in triplicate. Cell lysates are prepared and luciferase activity is determined using a luminometer. Agonist activity is assessed by comparing the luciferase activity from cells treated with compound alone to cells treated with either the agonist progesterone or aldosterone. Antagonist activity is assessed by comparing the luciferase activity of an EC50 concentration of progesterone or aldosterone in the absence and presence of compound. The EC50 (concentration that produced 50% of maximal response) for progesterone and aldosterone is calculated from dose response curves.
The following is a description of an assay for determining anti-diabetes and anti-obesity activity: The obese, diabetic ob/ob mouse is used to assess the anti-diabetes and anti-obesity activity of the compounds. Six to 10 week old ob/ob male mice (Jackson Labs, Bar Harbor, Me.) are dosed with test compound for 2 to 10 days. Plasma glucose levels are determined by measuring glucose from samples obtained by orbital bleeding. Glucose is quantitated using an Abbott Autoanalyzer (Abbott, Inc., Abbott Park, Ill.). Food intake is monitored on a daily basis by differential weighing.
The following is a description of an assay for determining the ability of a compound to inhibit glucocorticoid agonist induction of liver tyrosine amino transferase (TAT) activity in conscious rats:
Animals: Male Sprague Dawley rats (from Charles River, Wilimington Mass.) (adrenal-intact or adrenalectomized at least one week prior to the screen) b.w. 90 g are used. The rats are housed under standard conditions for 7-10 d prior to use in the screen.
Experimental protocol: Rats (usually 3 per treatment group) are dosed with test compound, vehicle or positive control (Ru486) either i.p., p.o., s.c. or i.v. (tail vein). The dosing vehicle for the test compounds is typically one of the following: 100% PEG 400, 0.25% methyl cellulose in water, 70% ethanol or 0.1N HCl and the compounds are tested at doses ranging from 10 to 125 mg/kg. The compounds are dosed in a volume of 1.0 ml/100 g body weight (for p.o.) or 0.1 ml/100 g body weight for other routes of administration . Ten minutes after the administration of the test compound, the rats are injected with dexamethasone (0.03 mg/kg i.p. in a volume of 0.1 ml/100 g) or vehicle. To prepare the dexamethasone dosing solution, dexamethasone (from Sigma, St. Louis, Mo.) is dissolved in 100% ethanol and diluted with water (final: 10% ethanol:90% water, vol:vol). Groups treated with vehiclexe2x80x94vehicle, vehicle-dexamethasone, and Ru486-dexamethasone are included in each screen. The compounds are tested vs. dexamethasone only. Three hours after the injection of dexamethasone the rats are sacrificed by decapitation. A sample of liver (0.3 g) is excised and placed in 2.7 ml of ice cold buffer and homogenized with a polytron. To obtain cytosol the liver homogenate is centrifuged at 105,000 g for 60 min and the supernatant is stored at xe2x88x9280xc2x0 C. until analysis. TAT is assayed on 100 ul of a 1:20 dilution of the 105,000 g supernatant using the method of Granner and Tomkins (Methods in Enzymology 17A: 633-637, 1970) and a reaction time of 8-10 minutes. TAT activity is expressed as umol product/min/g liver.
Interpretation: Treatment data are analyzed by using analysis of variance (ANOVA) with protected least significant difference (PLSD) post-hoc analysis. Compounds are considered active in this testif the TAT activity in the group pretreated with compound prior to dexamethasone administration is significantly (P less than 0.05) decreased relative to the TAT activity in the vehicle-dexamethasone treated group.
The following is a description of an assay for determining the effect of a compound on two typical genes that are upregulated during an inflammatory response. This assay, the glucocorticoid inhibition of IL-1 (Interleukin-1) induced MMP-1 (Matrix Metalloproteinase-1) and IL-8 (Interleukin-8) production in human chondrosarcoma cells, is conducted as follows: SW1353 human chondrosarcoma cells (obtained from ATCC) from passage 12 through passage 19 are used in a 96 well format assay. Cells are plated at confluence into 96 well plates in DMEM (Dulbecco""s Modified Eagle Medium) with 10% fetal bovine serum and incubated at 37xc2x0 C., 5% CO2. After 24 hours, serum containing media is removed and replaced with 200 ul/well DMEM containing 1 mg/L insulin, 2 g/L lactalbumin hydrosylate, and 0.5 mg/L ascorbic acid and returned to incubation at 37xc2x0 C., 5% CO2. The following morning, the serum free media is removed and replaced with 150 ul/well fresh serum free media containing +/xe2x88x9220 ng/ml IL-1 beta, +/xe2x88x925 nM dexamethasone, +/xe2x88x92compound. All conditions are completed in triplicate using only the inner 60 wells of the 96 well plate. Outside surrounding wells of plate contain 200 ul of serum free DMEM. Plates are incubated at 37xc2x0 C., 5% CO2. At 24 hours after addition of IL-1, 25 ul of sample from each well is removed under aseptic conditions for IL-8 production analysis. Samples are stored at xe2x88x9220xc2x0 C. until time of analysis. IL-8 production is assessed using the Quantikine human IL-8 ELISA kit from RandD Systems (D8050) on samples diluted 60-fold in RD5P Calibrator Diluent, following the manufacturer""s protocol. The percent of the average IL-1 control is determined for the average of each of the triplicate samples following subtraction of the average signal from untreated cells. IC50""s are determined from log linear plots of the percent of control versus the concentration of inhibitor. At 72 hours after IL-1 addition, the remaining media is removed and stored at xe2x88x9220xc2x0 C. until time of MMP-1 production analysis. MMP-1 production is assessed via the Bio-Trak MMP-1 ELISA kit from Amersham (RPN2610) on 100 ul of neat sample following the manufacturer""s protocol.
The percent of the average IL-1 control is determined for the average of each of the triplicate samples following subtraction of the average signal from untreated cells. IC50""s are determined from log linear plots of the percent of control versus the concentration of inhibitor. Dexamethasone has proven to be a good positive control inhibitor of both IL-8 and MMP1 expression (IC50=5nM).
The following compounds of the present invention are preferred:
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-N-(4-pyridinylmethyl)-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-N-(2-pyridinylmethyl)-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-N-(3-pyridinylmethyl)-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
carbamic acid, [2-(dimethylamino)ethyl]-, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl ester,[4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-N-pyrazinyl-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(1-propynyl)-7-(4-pyridinylmethoxy)-, [2R-(2xcex1,4axcex1,10axcex2)];
2-phenanthrenol, 1,2,3,4,4a,9, 10, 10a-octahydro-4a-(phenylmethyl)-2-(1-propynyl)-7-(2-pyridinylmethoxy)-, [2R-(2xcex1,4axcex1,10axcex2)];
2-phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(1-propynyl)-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-propyl-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-N-(2-pyridinylmethyl)-, [4bS-(4bxcex1,7xcex1,8axcex2)]-;
2-phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-2-(3,3,3-trifluoropropyl)-, [2S-(2xcex1,4axcex1,10axcex2)]-;
2-phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-3-pyridinyl) methoxy]-4a-(phenylmethyl)-2-(3,3,3-trifluoropropyl)-,[2S-(2xcex1,4axcex1,10axcex2)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(3,3,3-trifluoropropyl)-, (4bS,7S,8aR);
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-methyl-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-, (4bS,7R,8aR)-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-methyl-4b-(phenylmethyl)-N-3-pyridinyl-, (4bS,7R,8aR)-;
2-phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-3-pyridinyl) methoxy]-4a-(phenylmethyl)-2-(trifluoromethyl)-, (2R,4aS,10aR)-; and
2-phenanthrenecarboxamide, 4b, 5, 6, 7, 8, 8a, 9, 10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(trifluoromethyl)-, (4bS, 7R, 8aR)-.